| 00:02 | This is lecture 10 of Neuroscience and second lecture on neural transmission. And |
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| 00:11 | already learned quite a few important and things and in particular how this doesn't |
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| 00:20 | just at all. It's also quite , right? But we discussed the |
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| 00:30 | , for example, between amino Oh see, we discussed the differences |
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| 00:40 | some of the major subtypes of We talked about chemical neurotransmission, ep |
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| 00:49 | mediated by glutamate IP SPS mediated by uh release and chloride influx. Uh |
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| 00:58 | compared these amino acid neurotransmitters to amine . And we spoke about how amine |
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| 01:09 | are expressed in the confined regions or without different parts of the brain, |
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| 01:15 | small number of cells. But they'll synthesizing all of these different supposed uh |
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| 01:21 | uh respectively, dopamine, dopamine uh serotonin serotonergic cells and different |
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| 01:29 | And from there, these projections are to innervate broad areas of the brain |
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| 01:35 | also the final form, there are gap junctions. So these electrical junctions |
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| 01:42 | we spoke about the importance of gap and fast neural transmission and being able |
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| 01:49 | have bidirectional conductance without any delay, also being able to pass small molecules |
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| 01:57 | secondary messengers between the south and serve significant function when there is an input |
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| 02:04 | the neural network to synchronize the cells the individual neurons and the firing or |
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| 02:10 | output of that network projected onto the interconnected parts of the brain. Uh |
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| 02:19 | synopsis are diverse by where they they're also diverse in their shape. |
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| 02:23 | One axonal terminal can have 10 postsynaptic pre synoptic active zones targeting 10 postsynaptic |
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| 02:34 | . And uh we also discussed this cool technique of three dimensional imaging of |
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| 02:44 | and dendritic structures uh throughout the spines the importance of that. Then we |
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| 02:53 | about the neuromuscular junction. And when talked about neuromuscular junction, we highlighted |
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| 02:59 | things about this particular synapse. It's excitatory. This motor derm releases acetyl |
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| 03:07 | . And when you have activation of single cyn, that's strong enough to |
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| 03:14 | the all the control and that's always a causal change of flu and also |
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| 03:18 | higher in altitude. And so why it all exciting for me? Because |
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| 03:24 | of GIN is the only air transmitted to not the only neurotransmitter receptor that |
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| 03:32 | the cells is nicotinic acetyl coan So, nicotinic acetylcholine receptors will cause |
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| 03:39 | initial depolarization and they're located closer to pre synoptic terminals in those junctional faves |
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| 03:50 | uh they will acetyl colum receptor activation produce that employee potential. Ok. |
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| 04:00 | these are very large potentials and they always end up in the generation of |
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| 04:09 | skeletal muscle contraction, which is going be a little bit longer in action |
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| 04:15 | . So, depolarization comes through nicotinic receptor channels, the nicotinic acetylcholine receptor |
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| 04:26 | . When two molecules, when two molecules bind to the channel, why |
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| 04:34 | it depolarizing? Because it allows the of sodium. So you have two |
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| 04:42 | molecules binding it obviously on the outside the inside, you'll have influx of |
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| 04:50 | . That is what is going to for that massive plate potential depolarization. |
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| 04:58 | in addition to conducting sodium, these , receptor channels are also gonna allow |
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| 05:06 | potassium to e flux to come And that's the repolarization part of the |
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| 05:13 | potential. So what you're looking at the isolated amply potential shape. But |
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| 05:20 | , as soon as that potential, soon as that ization crosses the threshold |
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| 05:28 | indicated here, there will be an potential in the muscle oath. So |
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| 05:36 | are acetylcholine channels and once they depolarize of the muscle membranes and muscle |
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| 05:45 | they will open up voltage gated sodium potassium channels and causing that prolonged action |
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| 05:51 | and skeletal muscle. So we spoke different types of neurotransmitters. So we |
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| 05:59 | understand for example, that uh amino neurotransmitters are packaged in vesicles. And |
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| 06:07 | spoke about two different shapes of vesicles symmetries and the synopsis. And so |
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| 06:14 | have to know which one is which one is inhibitory. We also |
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| 06:20 | about these other, what we refer as dense four vesicles. OK. |
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| 06:26 | you cannot easily see through them. kind of like darker looking in appearance |
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| 06:32 | those will be housing neuropeptides. So we have these vesicular storage, |
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| 06:39 | So we have neurotransmitters of peptides that stored in vesicles, amino acids and |
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| 06:47 | are stored in the vesicles, peptides stored in these dense core vesicles. |
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| 06:53 | we'll discuss in greater detail in a . Well, we also talked about |
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| 06:58 | other substances, adenosine and A Uh no and co carbon monoxide and |
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| 07:07 | oxide and endocannabinoid molecules. And these what you would call nontraditional classical |
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| 07:15 | And we don't necessarily understand very well release by of A TP exactly how |
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| 07:24 | happens. But it does have some of a transportation across plasma membrane. |
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| 07:30 | it is important communication between neurons and also. And uh glia can release |
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| 07:38 | TP on other glia. So microglia release a TP on astrocytes and activate |
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| 07:46 | . So, and it's not very studied like the vesicular release in astrocytes |
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| 07:50 | , of A TP. So there's lot of work that we need to |
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| 07:55 | to do. But what is very is that some of these other molecules |
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| 07:59 | an LCL and and the cannabinoids are soluble. And that means that they |
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| 08:04 | be stored inside the vesicles because the membranes are composed of phospholipids, phospholipid |
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| 08:12 | . So they would essentially dissolve and means that there is a different mechanism |
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| 08:16 | producing them because as soon as you them within the cell, they will |
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| 08:22 | spread through the membrane and activate their receptors. So there has to be |
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| 08:27 | different mechanism which turns on the biosynthesis these molecules. And also a different |
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| 08:33 | by which these molecules signal inside the and direction in which they signal these |
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| 08:40 | dense core vesicles. And the difference that most of what happens with neuropeptides |
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| 08:47 | very tightly tied to what is happening the level of the some of the |
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| 08:53 | . So you have active peptide, neurotransmitter, uh uh vesicle dens or |
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| 09:02 | that comes about from the precursor it gets loaded. And these are |
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| 09:08 | referred to secret Granules. And for , if you have an action |
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| 09:14 | a single action potential and depolarization and presynaptic terminal and the Saxon terminal will |
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| 09:22 | in exocytosis in the vesicle neurotransmitter However, that's not going to cause |
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| 09:29 | release of neuropeptides. So, neuropeptides typically activated with heightened levels of activity |
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| 09:37 | there is uh a lot of sustained . So, not just one action |
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| 09:41 | but repeated or trains of action that's when they get activated, that's |
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| 09:46 | they're being transported into the synapse. in our previous images, we saw |
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| 09:52 | uh they are indeed located in these terminals and they're co localized, the |
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| 09:58 | means that they are present there together defense corps of vesicles with secret gran |
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| 10:03 | present there together with neurotransmitter vesicles in preoptic terminal. So they're co localized |
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| 10:09 | , we already looked at it. the interesting thing is that secret Granell |
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| 10:13 | quite often may not reach the external and can be released along the external |
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| 10:21 | . So there's spatial release and the therefore of where they are present and |
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| 10:28 | they're released along the axon is not precise as with neurotransmitter vesicles. |
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| 10:36 | So those are some of the So most of the vesicles that get |
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| 10:41 | here, they actually just get recycled in the pre synoptic terminal, sometimes |
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| 10:46 | get returned to the early endo but it still is mostly all happening |
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| 10:51 | the pre synoptic terminal and dense cor by synthesis transport and then release requires |
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| 10:59 | conditions and doesn't have as much, know, spatial specificity. So there |
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| 11:03 | two things that need to happen in for neurotransmission to take place. We |
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| 11:08 | talked about how if there is a enough depolarization, uh then the cell |
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| 11:15 | produce an action potential, action potential get produced at the Axon Hillock, |
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| 11:22 | action potential will get regenerated at each of around here until it reaches the |
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| 11:28 | terminal. So you need the action and you need this large depolarization. |
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| 11:36 | is one of the things you need order to cause exocytosis. The second |
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| 11:41 | that you need is that once that potential arrives in the pre synoptic terminal |
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| 11:47 | that, what I mean is what arrives and says hello, when this |
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| 11:51 | very quick depolarization of 100 mill balls the synoptic terminal here it opens up |
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| 12:01 | gated calcium channels. So you already about voltage gated sodium channels and potassium |
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| 12:07 | and mediating the rising for sodium and following for potassium phases of the action |
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| 12:13 | , right? And now you have synaptic terminal, you have a lot |
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| 12:19 | voltage gated calcium changes. So there's strategy here, neuron has a |
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| 12:25 | Neuron has a strategy of placing a of voltage gated sodium and potassium channels |
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| 12:31 | the axon hillock. And at each of Ron beer through a produced action |
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| 12:37 | , you will also of course have gated sodium and potassium channels at the |
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| 12:42 | terminal, no doubt because that action has to be there at the external |
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| 12:47 | . But now you're introducing voltage gated channels which are not present or in |
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| 12:53 | very uh uh uh uh or expressed very, very, very small |
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| 12:59 | And and uh and along like for , uh nodes of wrong deer, |
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| 13:04 | you'll have high levels and densities of voltage gated calcium channels being expressed right |
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| 13:11 | what we call the active zones. , influx of calcium is going to |
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| 13:15 | for the protein complex that we referred as vesicular protein complex. A lot |
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| 13:20 | times as V snare, we'll have interact with the membrane or t snare |
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| 13:28 | complex here. So you have this protein complex interactions that allow for the |
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| 13:34 | membrane of the vesicle because it is phospholipid bilayer on its own. So |
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| 13:39 | bilayer has to fuse with a bilayer . And as it fuses, it |
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| 13:45 | release the content the vesicles into the block and then it will get endocytosis |
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| 13:51 | and refill the back within this pre terminal. So in science, we |
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| 13:59 | about how it's really important to visualize . And in this course, we'll |
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| 14:05 | talk about how it's also very important visualize neuronal activity. Because to |
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| 14:13 | we talked about mostly morphology and we about of course, like cellular |
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| 14:20 | we didn't really talk much about molecular or transcript tos, for example, |
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| 14:26 | maybe you can tell us something about states of activity within the cells. |
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| 14:31 | the ultimate is really to be able visualize an image activity of neuronal networks |
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| 14:38 | neurons, individual neurons and individual synapses individual vesicles and individual proteins in a |
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| 14:48 | synapse. And that can be done days because we have m microscopes that |
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| 14:53 | powerful enough have really good resolution. we have a lot of different |
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| 15:00 | Some of these dyes could be calcium . That means that something about the |
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| 15:06 | of that dye that you apply on tissue is going to change as calcium |
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| 15:12 | changes some of the dyes are sodium potassium sensitive. That means that sodium |
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| 15:18 | dye, that means something about the of that dye. You can apply |
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| 15:23 | dyes on the tissue. For It's the same thing you can apply |
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| 15:28 | on the tissue. It's little dye and you can shine a light on |
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| 15:34 | dye molecules and they will reflect a amount of light and the amount of |
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| 15:40 | that it reflects from that tissue, gonna represent the concentration of calcium. |
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| 15:46 | imagine more light reflected more calcium, light reflected less calcium, just in |
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| 15:51 | rudimentary terms. It doesn't necessarily have linearity or directionality that I'm referring to |
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| 15:57 | now. But calcium. So you can have calcium imaging also, |
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| 16:04 | can also have genetically expressed voltage indicators we call get or jets. And |
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| 16:14 | is really cool because when you apply dye on the tissue guess where that |
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| 16:20 | penetrates. It's sort of like uh could be comparable to nissel stain. |
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| 16:26 | will actually infiltrate or penetrate the membranes the inside of the cells, all |
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| 16:31 | the cells. So if it's lipid dye intracellular will go inside. If |
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| 16:35 | a membrane bound diet, it will to all of the membrane. So |
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| 16:39 | doesn't give you much specificity. And some of the genetically encoded voltage |
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| 16:46 | you can drive the expression of these indicators. So what does it |
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| 16:51 | Voltage indicators? You can instead of calcium or sodium or potassium individual |
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| 16:58 | you can track changes in the membrane . So that's voltage indication in general |
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| 17:06 | , hyper polarization. As we depolarization and hyper polarization, they can |
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| 17:11 | and you'll learn in the next lecture hyper polarization will have conductance of both |
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| 17:16 | and potassium. So if you just potassium, you would miss the uh |
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| 17:22 | polarization of council chloride. OK. you can also just measure voltage |
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| 17:28 | And as you know, membrane potential membrane voltage is a reflection of Goldman |
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| 17:35 | which is a reflection of at least or three ionic species. And if |
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| 17:41 | of these has really high permeability, can come into play and become |
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| 17:47 | not just sodium and potassium given the the specific conditions. So you can |
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| 17:53 | image voltage. And the advantage of genetically encoded voltage indicators is that you |
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| 17:58 | drive their expression tag them to specific sensitive domains on the channels. And |
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| 18:08 | can also express them within specific subsets cells. So for example, you |
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| 18:15 | to express a voltage indicator or calcium dyre indicator. In this case, |
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| 18:22 | you're doing genetic expression just in the that supplies, let's say dopamine just |
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| 18:34 | the ventral tegmental and substantial mile. so that that gives you a lot |
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| 18:40 | specificity. So now you can get imaging potentially not only activity only in |
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| 18:47 | area of the brain but in specific of cells. Remember we have different |
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| 18:52 | of cells. They are different functionally importantly, but also in many other |
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| 18:57 | that we studied like morphologically also. in this image, what we have |
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| 19:04 | uh early work of calcium sensitive dye uh by Rodolfo Lina's work. Uh |
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| 19:13 | what Rodolfo Lina's lab has showed is if they were imaging calcium and this |
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| 19:19 | you a picture now of calcium So in this case, these heat |
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| 19:24 | , the red represents high calcium concentration the blue represents normal or low calcium |
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| 19:34 | . And so what they saw is there are these very clearly defined peaks |
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| 19:41 | when neurons are addressed and they're imaging concentrations, prey not the calcium |
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| 19:49 | And this is addressed, we have very clearly defined mountain tops and the |
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| 19:55 | mountain range and then during the train action potential. So during intensive stimulation |
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| 20:03 | arrives at the external terminal, what see is this whole structure that you |
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| 20:09 | here. Now all glows red. you have massive influx of calcium |
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| 20:16 | you have a lot of calcium and lose the spatial specificity on where that |
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| 20:21 | is located. And you also have high and sustained concentrations and rises in |
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| 20:29 | concentrations. So now what's interesting is remember we talked about how neurotransmitter vesicles |
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| 20:40 | primed and docked at these active presynaptic zones. And so this structure |
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| 20:46 | actually showed that voltage gated calcium channels grouped and the higher densities of them |
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| 20:55 | expressed right next to the active And that's because of this necessity of |
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| 21:01 | influx so that you can have No, this is really important. |
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| 21:10 | these are the presumed calcium channels, looking these uh presynaptic calcium channels and |
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| 21:17 | those channels during the stimulation have shown different levels and concentrations of calcium. |
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| 21:23 | really important because you can measure it in a single synapse. And you |
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| 21:28 | look at the calcium dynamics, spatial we call spatial and temporal. So |
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| 21:34 | temporal dynamics of calcium fluctuations during pre vesicle release. Yeah, everybody with |
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| 21:45 | . Can you repeat it? So we have this uh calcium channels |
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| 21:55 | , you're looking at the pre synoptic active zones and once you have the |
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| 22:03 | potentials, you have the vesicles So the vesicles came from behind the |
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| 22:10 | , behind the screen and then during stimulation they used in. So you're |
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| 22:14 | at the crater, the crater is with neurotransmitter get released. Uh And |
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| 22:22 | you can see how these presynaptic calcium are uh very closely dotted here right |
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| 22:30 | the line of uh of uh of transmitter vs release. Uh we have |
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| 22:41 | different dyes. And advantage of some these dyes is that they can report |
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| 22:46 | things like calcium, sodium voltage. of them can do it in |
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| 22:50 | very fast manner. So some of are directly like voltage sensitive dyes are |
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| 22:56 | to changes in voltage directly. And some of them have single cell resolution |
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| 23:02 | even single molecule, single protein resolution some instances. So this process of |
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| 23:10 | , you have calcium influx and then you have calcium influx on this D |
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| 23:16 | , you have calcium sensors. So protein complex will sense influx of |
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| 23:23 | The calcium proteins will interact uh The the uh these snare proteins will |
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| 23:30 | with the T snares in the Uh They will fuse and incorporate the |
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| 23:38 | into the overall neuronal membrane. The neurotransmitter vesicle gets recovered by endocytosis. |
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| 23:47 | gets covered with clatter coated with Once it goes into this position, |
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| 23:54 | , it gets recognized as an empty , it gets acidified. This high |
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| 24:00 | gradient is also going to drive transport neurotransmitters into the vesicle where it gets |
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| 24:08 | again, very close to the active gets docked. You have to have |
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| 24:14 | certain amount of energy in the form a TP to oversee this whole |
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| 24:18 | So there will be mitochondria and energy dedicated to vesicular release. Quite a |
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| 24:23 | of it. You have a primed . So it's sitting in this position |
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| 24:28 | is primed, it hasn't fused It is now going to sense influx |
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| 24:33 | calcium and what can happen in some in the CNS and doesn't happen in |
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| 24:41 | PNS and the neuromuscular junctions. But the CNS, you may have this |
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| 24:47 | opening of the what we call the form and only partial movies with |
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| 24:54 | And it actually can return into this here and go through the cycle for |
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| 25:01 | into dark and to prime it And so this is referred to as |
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| 25:05 | and run. So just kiss glut plasma membrane of the neuron and it |
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| 25:11 | away to get refilled again. in other instances, and if you |
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| 25:16 | strong enough depolarization, stimulus action potential trains them, you will cause full |
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| 25:23 | of the vesicle and therefore full uh content release into the synaptic cleft. |
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| 25:31 | yet, as I mentioned in some instances, these used up vesicles will |
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| 25:36 | cycled back into the early end of where they will essentially get reprocessed into |
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| 25:43 | vesicle, getting ready to be filled neurotransmitter in the presynaptic terminal. So |
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| 25:51 | again, a reminder for excitatory we'll talk about glutamate and glutamate binding |
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| 25:59 | glutamate receptor channels causes influx of And also like in nicotinic acetyl receptors |
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| 26:06 | reflux of potassium, therefore responsible for SPS, excited to synoptic potentials and |
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| 26:14 | of Gaba binding of Gaba. In instance, it's shown gabba a receptor |
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| 26:20 | . So these are ionotropic channels because uh A molecule will actually cause the |
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| 26:27 | of an ion. So, ionotropic that channel, an influx of fluoride |
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| 26:32 | account for the IP sp the inhibitory potentials. There's this thing that when |
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| 26:41 | looked and already talked about this from very beginning when we look at the |
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| 26:48 | , the synoptic responses, we see these responses are graded, some of |
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| 26:53 | are larger, some of them are in size, both in hyper polarizing |
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| 26:58 | depolarizing direction. And only if they're enough to reach the threshold of the |
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| 27:06 | potential that will cause this massive action generation. OK. So now this |
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| 27:16 | where quite often we can look at smallest possible. So now you recorded |
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| 27:23 | trace, you recorded that trace and trace has all sorts of different |
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| 27:30 | And you're gonna look now or the depolarization that you find here. And |
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| 27:35 | gonna identify these as the smallest Those are typically going to be referred |
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| 27:42 | miniature potentials or uh elementary units synaptic which are elementary units of synaptic |
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| 27:50 | They will have a quantum of neurotransmitters the vesicles. And that quantum, |
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| 27:58 | for example, the acetylcholine synapses, to 4000 chemical molecules or transmitters inside |
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| 28:06 | vesicle and say, OK, that's . It's really indivisible, it's really |
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| 28:11 | , it's 2000 to 4000. There's range, of course, it's |
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| 28:17 | But for the most part, you , 2000 is almost enough and sufficient |
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| 28:21 | do what 4000 could do even more a way because not all of the |
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| 28:28 | often don't bind to all of the . So there's more in that |
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| 28:33 | so to speak, but it's also between five and 20,000 or five and |
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| 28:40 | . So it it is within the of this quantum. And when you |
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| 28:45 | one content of one vesicle in your , you'll see these really miniature potentials |
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| 28:52 | we talked about how these miniature potentials going to be on the order of |
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| 28:59 | half a mill. So these are SPS or mini EPS PS. So |
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| 29:08 | happens if you find uh an EPSP when you measure this small epsp, |
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| 29:17 | actually one millivolt in size. And you find another one that is, |
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| 29:28 | say five millivolts inside. So that you that if this is my |
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| 29:36 | that means it's one vesicle and it's a millivolt. If I release two |
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| 29:42 | , it's gonna be incremental. So now going to be with two vesicles |
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| 29:48 | depo is gonna be one millivolt. so with 10 vesicles of depolarization is |
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| 29:54 | be five millivolts and synopsis or So you can kind of understand how |
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| 30:02 | synopsis and how many vasic are being using this quantum analysis and looking at |
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| 30:09 | miniature postsynaptic responses. So this is different about the brain again, is |
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| 30:18 | the potential will always surpass this But here you will have to activate |
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| 30:24 | we talked about tens of excitatory synopsis order to reach the threshold for that |
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| 30:31 | . Yeah, there any endplate potential be graded at all. It, |
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| 30:37 | , it, it, it is to a certain degree in the sense |
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| 30:41 | even the action credential, when it 100 millivolts, it will fluctuate a |
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| 30:46 | bit. It will be 98 and 100. So the same with the |
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| 30:56 | , EPSP can be 0.52 for miniature 0.48. The Epp also can be |
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| 31:04 | millivolts or 43. The point with is that it is always large enough |
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| 31:12 | cross the threshold. Yeah. So gonna look at the acetylcholine life |
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| 31:22 | Uh Are we really gonna talk about here? I guess so or did |
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| 31:29 | jump into the wrong presentation? Let check something real quick uh slides. |
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| 31:42 | so we will actually come back and a lot more about, I mean |
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| 31:49 | , but we will start by looking acetylcholine life cycle and then we will |
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| 31:55 | about kind of a life cycle of lot of these different molecules. And |
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| 32:04 | let's talk about acetylcholine as a sort an example here, something that you're |
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| 32:09 | need to know for the quiz and the exam, acetylcholine synthesized in those |
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| 32:16 | neurons and they synthesized from cline acetyl coming together with choline acetyl transferase. |
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| 32:23 | they have to chat, we chat and they form ach and then you |
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| 32:30 | ach transporter. So what does that that you have vesicular transporters? You |
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| 32:41 | the secular transporters. Those are the that are going to upload, transport |
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| 32:52 | chemicals into the vesicles glutamate, you're have glutamate, vesicular transporter. Gaba |
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| 32:59 | vesicular transporter, dopamine, dopamine you'll have acetylcholine transporter in the |
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| 33:07 | And that's the difference in the CNS acetylcholine gets released. Ok. In |
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| 33:14 | CNS, acetylcholine can target nicotinic and receptors. So, in the neuromuscular |
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| 33:23 | , we talked about nicotinic only. were the only, those were the |
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| 33:27 | excited to receive gold receptors in the junction. In the CNS, you |
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| 33:34 | nicotinic, these are receptor channels and that are metabotropic. So they're not |
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| 33:42 | channels, they are G protein coupled . So, acetylcholine in the |
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| 33:49 | cyl choline and the CNS signals through acetylcholine receptors and muscarinic acetylcholine receptors. |
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| 34:05 | acetylcholine is released in the neuromuscular it causes depolarization through nicotinic receptor sound |
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| 34:13 | in the CNS through the nicotinic acetylcholine . It will also cause depolarization but |
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| 34:19 | smaller depolarization. So it doesn't play much of a significance in depolarization like |
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| 34:26 | employ potential neuromuscular junction because just the it is and then it gets broken |
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| 34:34 | by acetylcholinesterase into choline and acetic It's broken down into cline and acetic |
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| 34:42 | and then cline has a transporter. you have another transporter, a neurotransmitter |
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| 34:53 | , we call it reuptake, we transporter and it's re uptaking acetylcholine and |
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| 35:08 | it back into the presynaptic terminal. there again, it goes through the |
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| 35:14 | of being synthesized, uh being uploaded vesicle release, targeting poop receptors. |
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| 35:26 | you also may have heard uh about the tritium botulinum or about a line |
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| 35:38 | neurotoxins. Has anybody heard of So that can, that can happen |
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| 35:46 | you have bacteria that if you have canned or stored or expired canned food |
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| 35:55 | often, you can have bacteria that form uh clostridium box of iron and |
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| 36:03 | . People can get really seriously poisoned that uh can be even deadly. |
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| 36:10 | what happens is that it serves as blocker uh uh neuromuscular acetylcholine release. |
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| 36:23 | you'll also see why that's important and targets that protein protein complex. Remember |
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| 36:30 | talked about the vesicular v snare t . So this the snare protein |
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| 36:37 | So it targets the proteins. So what it does is these botulinum |
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| 36:46 | here which come in different subtypes and they depicted here as little Sharkey and |
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| 36:53 | little Sharkey will chew up the protein complex interaction and not allow for the |
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| 37:02 | to fuse with the plasma membrane. this is the bottom line of |
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| 37:17 | The reason why I like to talk these things within the broader context always |
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| 37:23 | because they have a natural substance that kill you in, in a poorly |
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| 37:28 | stored canned food. But if you that natural substance in a controlled environment |
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| 37:36 | controlled sterile preparations, it becomes a . So you have to know the |
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| 37:44 | , you have to know the size injection. And for medicine purposes, |
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| 37:50 | is approved for injections, interestingly very to, to the, to the |
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| 37:58 | kind of uh injections that we were talking about the wrinkle lines. Uh |
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| 38:04 | these are very helpful and I think close to 200,000 patients is FDA approved |
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| 38:11 | of chronic migraines, severe migraines. it's interesting because it would block cholinergic |
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| 38:19 | , cholinergic neural transmission essentially. And helps people that suffer from chronic |
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| 38:27 | How does that work with wrinkles? , it's quite simple. The more |
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| 38:32 | strain and move your facial muscles over age, your skin stretches and creates |
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| 38:41 | and what Botox does and it's you know, something that people |
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| 38:47 | So this both injections for migraine treatments for beauty purposes, it's something that |
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| 38:54 | repeat typically every whatever often they can it typically. Uh but it just |
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| 39:03 | blocks acetylcholine release on activating the the face muscles. And it essentially |
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| 39:14 | the appearance of the wrinkle because those are not being activated. We're not |
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| 39:19 | about like fillers. I think those somewhat different things where people injecting their |
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| 39:24 | and stuff. But e even for Botox injections around the face and mouth |
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| 39:31 | , people after the treatment quite often , but we will control, speak |
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| 39:36 | well because it can control muscles very uh and move everything. So it |
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| 39:42 | a minute for them to come out it. All right. Uh This |
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| 39:49 | the mode of action. A pylos release. We have a lot of |
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| 39:55 | in nature, bacteria, spiders, , and also we have people that |
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| 40:01 | a lot of toxins and toxic substances use them for different purposes. Um |
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| 40:08 | from black widows spider contains latro So you remember we talked about certain |
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| 40:17 | spider toxins or scorpion toxins. We about scorpion toxin. When we refer |
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| 40:24 | uh potassium channels. It's uh in case, it's uh the venom with |
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| 40:30 | lat toin. It's a protein molecule puncture cells and it depletes calcium. |
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| 40:39 | it doesn't act like sharkies. it will puncture the cells and make |
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| 40:43 | holes inside the membrane. And it have uh basically all of the calcium |
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| 40:51 | uh and can facilitated neuro neurotransmitter release calcium. It's really weird because there's |
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| 40:59 | calcium on the inside than on the than the inside. But yet these |
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| 41:06 | must puncture massive holes somehow deregulate calcium at the same time, facilitate neurotransmitter |
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| 41:15 | . Taiwanese cobra has alpha munger which instead of targeting the presynaptic mechanism |
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| 41:24 | release, it actually targets psyop So, different toxins of different |
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| 41:31 | If we're looking at cholinergic system, will target different parts of the |
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| 41:35 | Some of them vesicular release, calcium, presynaptic calcium depletion, others |
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| 41:42 | target the phos receptors. Uh and will cause desensitization of these poop acetyl |
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| 41:50 | receptors and can lead to respiratory muscle . So it's not just an effect |
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| 41:57 | the CNS, but it's typically a of the toxins that will interact with |
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| 42:02 | channels or with the targets. And CNS will also be interacting with the |
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| 42:07 | channels of targets and uh diaphragm and respiratory muscles and, and cardiac muscles |
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| 42:16 | such. So, different different Now, what do people have to |
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| 42:22 | with it? People make organic phosphates a chemical weapon. Sarin Soman is |
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| 42:31 | brand name. Uh and why is important? So, organa phosphates uh |
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| 42:39 | like sarin gas are also known as gasses. And you may have heard |
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| 42:45 | a big story going on right now the leader of the opposition in |
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| 42:52 | uh Navalny is mysteriously collapsed and died his walk in the Russian prison. |
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| 43:02 | However, uh three or so years , he was also poisoned by nerve |
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| 43:09 | that Russians call Novik and he nearly . And that was a big international |
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| 43:17 | if you didn't see three years Uh if you open any front page |
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| 43:22 | , especially uh couple of days immediately after his, his death, |
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| 43:29 | a lot of discussions about uh why authorities wouldn't release his body now for |
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| 43:35 | weeks. And there's a speculation that how long it takes for the tissues |
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| 43:40 | be cleaned off certain toxic communications and like that. So it's an ongoing |
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| 43:46 | and they bear some resemblance, these gasses and nerve toxins. They bear |
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| 43:52 | resemblance to, to China and their of action. And siren is a |
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| 44:00 | weapon. So it's not allowed by convention to, to use these chemical |
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| 44:05 | , but we saw them, we them again and war in Syria actually |
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| 44:10 | they were used on, on the in Syria, which is horrible. |
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| 44:16 | not necessarily siren may be a different of a chemical weapon. What it |
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| 44:21 | , it's a irreversible acetylcholine esterase in terms. And so this is another |
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| 44:28 | that remember we talked about agonist and agonist is something that opens the |
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| 44:34 | antagonists is something that closes the And then most of the substances like |
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| 44:41 | , when they bound to the they're not gonna stay bound. |
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| 44:45 | so they're going to be reversible which means that they're gonna bind to |
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| 44:50 | channel, they're gonna change the confirmation the channel they're gonna hang out for |
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| 44:55 | however long for different substances and different . And then they're gonna dissociate in |
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| 45:00 | left. And that's when it's gonna again, uh broken down by en |
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| 45:07 | breakdown in case of a PSE COVID reuptake back in the presynaptic terminal. |
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| 45:13 | they're reversible. But if something binds , that's where, that's where it's |
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| 45:20 | irreversible. In this case, it's of acetyl colon estimates if you inhibit |
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| 45:29 | , what happens is that you're not down acetylcholine and that acetylcholine is lingering |
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| 45:38 | in the synapse and you're not breaking enough into Coline to be ret |
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| 45:44 | So you kind of uh affect the chain of this called anergic in this |
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| 45:52 | synapse. But the fact predominant effect that you will increase the amount of |
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| 45:58 | code within the synapse. How much that acetyl Colin is available would increase |
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| 46:05 | you block acetyl or if you inhibit can cause overabundance of acetylcholine acetylcholine. |
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| 46:14 | much of it can lead to acetylcholine desensitization. But that what we mean |
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| 46:21 | that receptors need to be bound and , bound and unbound. And they |
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| 46:28 | certain dynamical range for this interaction with chemical molecules. And if there's too |
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| 46:35 | of the neurotransmitter always being released, channel or that receptor channel says, |
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| 46:41 | know what I'm, I'm kind of I'm kind of tired, I'm not |
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| 46:44 | and maybe you need to increase even amount for me to react to |
|
| 46:50 | So this is really desensitization, uh cleaves acetylcholine to render it inactive |
|
| 46:58 | we talked about. Of course, Peron is an insecticide and sometimes you |
|
| 47:06 | see it here. When people go the outdoor world stores, there are |
|
| 47:13 | chemicals that are sprays that are So the guys that are into hunting |
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| 47:19 | fishing, they'll spray their overalls and gear without uh some of the similar |
|
| 47:27 | it's toxic in high doses. So , when you, when you look |
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| 47:31 | the insecticide, it kills something, know, it kills cockroaches in your |
|
| 47:35 | . You know, it's not recommended spray as a, as a body |
|
| 47:40 | , you know, um, now and this is all still related to |
|
| 47:47 | inhibition of season. Clyster pharmaceuticals. is inhibitors of sins. Those are |
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| 47:57 | medications. So most of the Alzheimer's , with the exception of Meine and |
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| 48:03 | new one that came online. most of the Alzheimer's medications target |
|
| 48:12 | So they're aceto colony and that tells that Alzheimer's disease and Alzheimer's disease, |
|
| 48:20 | have decrease in acetyl pill. So talked about how you have the pathology |
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| 48:29 | the neurofibrillary tangles because of the increased uh protein uh outside the cells. |
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| 48:38 | have formation of beta amyloid plaques because the over increased production and aggregation of |
|
| 48:45 | amyloids and formation of the plaques. the system. When we talk about |
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| 48:53 | systems, the system that gets affected Alzheimer's disease is acetylcholine system called anergic |
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| 49:01 | . That means that there are deaths these cholinergic neurons and neurons that supply |
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| 49:07 | the going into the brain and that's the best medication. So most of |
|
| 49:12 | Alzheimer's medications, all, in Alzheimer's medications are not cures, there |
|
| 49:18 | no cure for Alzheimer's all Alzheimer's medications slow down what we call the severity |
|
| 49:24 | the progression of the disease. It mean that they block the progression of |
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| 49:31 | disease, but they just slow it . And the success of Alzheimer's medications |
|
| 49:38 | quite often billed as a percentage. in the decrease ok percentage on the |
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| 49:49 | of the progression of the disease. it's decrease of prog progression by |
|
| 49:55 | Everybody in the pharma is really, happy. The newest one I think |
|
| 50:00 | , it's a 30% uh the US , but that's most of them are |
|
| 50:08 | the nest inhibitors. What's the The problem is these cells are dying |
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| 50:16 | sizes that are producing a single B A. So you're not stopping the |
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| 50:21 | of these neurons, you're not generating acetylcholine, you're just making more of |
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| 50:26 | available until there's none available at Because if you kill all of these |
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| 50:33 | neurons, there's no production of And now you can see how everything |
|
| 50:38 | this pathway is intertwined from bacteria to to medications, um muscular, skeletal |
|
| 50:50 | , uh facial muscle and also migraines are cns uh neurological disorder. It's |
|
| 50:59 | a headache, migraine is not a . It's a neurological disorder. It |
|
| 51:04 | a symptomology of extreme headaches in many . So, neuropharmacology, we are |
|
| 51:12 | interested in how these different substances. already talking about neuropharmacology. We're talking |
|
| 51:18 | where different substances will bind. Are gonna bind the pseudo receptor? Are |
|
| 51:24 | gonna bind to a PSE codeine vesicle complex? Are they gonna bind to |
|
| 51:32 | ? Nest erase and inhibit. So is what neuropharmacology is. You want |
|
| 51:37 | understand how different substances interact with different , channels and targets proteins in the |
|
| 51:48 | where they bind. So, when talk about the three dimensional structures, |
|
| 51:53 | can bind in different parts of these . And we talked about uh voltage |
|
| 51:57 | sodium channel. So this is where binds. For example, uh there's |
|
| 52:03 | areas where other molecules will bind to channel. So it's really a study |
|
| 52:08 | effects of drugs and nervous system, antagonists. We already talked about |
|
| 52:15 | So when we talk about acetylcholine, agonist for nicotinic acetylcholine receptor channels is |
|
| 52:25 | from tobacco. Uh the antagonist is . So if you apply curare on |
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| 52:33 | neuromuscular junction, this is in the of curare. The depolarization will never |
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| 52:39 | the threshold level to generate action But uh Curare is a receptor |
|
| 52:52 | Mhm What is? But a line talks in it blocks vesicle fusion, |
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| 53:01 | blocks vesicle release. So again, shows you different substances along this |
|
| 53:06 | You can manipulate the postsynaptic receptor. you can manipulate the presynaptic neurotransmitter release |
|
| 53:15 | block the active potential. And if have this defective neurotransmission and molecules and |
|
| 53:23 | have so many different molecules and chemicals your brain that can lead to neurological |
|
| 53:29 | . So we just talked about acetylcholine Alzheimer's disease. We didn't talk about |
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| 53:35 | necessarily or serotonin and Alzheimer's disease. talked about acetylcholine. Now, some |
|
| 53:43 | the cells will also have auto So this is an example of Gaba |
|
| 53:54 | . So you will have, for , Gaba that is being released |
|
| 54:00 | So you need influx of calcium. order for the vesicle to fuse and |
|
| 54:05 | Gaba binding Gaba A will cause influx fluoride and will cause the IP S |
|
| 54:13 | . But also in many instances, , in which case, it's actually |
|
| 54:21 | B receptors, another type of inhibitory channel. In this case, it's |
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| 54:28 | a channel, it's G protein coupled will be located presyn op and so |
|
| 54:34 | flux of calcium will be inhibited. these are referred to as Gaba V |
|
| 54:43 | receptors. So, the cli that Gaba and it has also receptors for |
|
| 54:48 | own molecule like Gaba. Even if metabotropic Gaba B receptor, this is |
|
| 54:54 | to as auto receptors. So the receptors quite often will inhibit the release |
|
| 55:01 | its own molecule and sort of a like a negative feedback or like a |
|
| 55:09 | like mechanism. So, we have built in mechanisms of neurotransmitter release. |
|
| 55:15 | the presynaptic side, we already have of these uh mechanisms that we're talking |
|
| 55:22 | regulating them with drugs. And we also auto receptors. So we have |
|
| 55:28 | receptors, but we also have presynaptic that are auto receptors for the same |
|
| 55:36 | when we talk about metabotropic signaling. when we talk about muscarinic acetylcholine |
|
| 55:43 | it's a metabotropic receptor. And when talk about metabotropic signaling, a |
|
| 55:51 | neurotransmitter will bind to the receptor and will not open the channel but activate |
|
| 55:57 | protein complex and it can activate a channel. It can also activate an |
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| 56:07 | or secondary messenger cascade downstream inside the and cause sometimes long lasting effects on |
|
| 56:15 | physiology and function of the cell If you recall have to integrate all |
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| 56:27 | that information, they have to integrate SPS and IP SPS and most neurons |
|
| 56:34 | have thousands of inputs. So imagine the EPSP is a plus and an |
|
| 56:40 | SP is a minus, you have integrate all of that information. So |
|
| 56:45 | getting 20,000 pluses and are they are you getting them all at the |
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| 56:50 | time where you can stack them linearly you getting 20,000 pluses over 100 milliseconds |
|
| 56:58 | 5000 minuses Gaba inputs over the same of time. So there are all |
|
| 57:04 | these dynamics uh of synaptic integration everywhere where you see the green dot is |
|
| 57:12 | receptor. So you have excitatory synopsis is inhibitory Synopsis Gaba. And this |
|
| 57:20 | job is to very quickly compute. is what neuronal computation is is that |
|
| 57:28 | has very extensive processes and complex morphology it will get bombarded by savory and |
|
| 57:36 | inputs along different parts of dendrite, basal soma. It has to compute |
|
| 57:45 | information very quickly and it is a computer. It does it within |
|
| 57:52 | usually within few to tens of It will make a decision whether it |
|
| 57:57 | produce an action potential or not. , how do you sum of these |
|
| 58:05 | SBS. OK. And recall that depolarize this membrane and you can have |
|
| 58:15 | membrane. But if you activate three at the same time, this response |
|
| 58:21 | gonna be three times or five This response is gonna be five times |
|
| 58:25 | size. It's a good way, good strategy for this neuron to integrate |
|
| 58:30 | information is through spatial summation where the stimulus or uh or the stimulus arises |
|
| 58:38 | about the same time but across different of the sapo dendrite and allows you |
|
| 58:45 | produce a much stronger signal. in temporal summation, let's say you |
|
| 58:54 | one synapse. But here instead of one action potential in each axon, |
|
| 59:00 | produce a train of action potentials in axon. And so these action potentials |
|
| 59:09 | arrive one, 23 millisecond delay, millisecond delay because you have to re |
|
| 59:17 | the membrane. Third one arrives This is called this temporal summation. |
|
| 59:24 | this case, as you can see signal, the response in temporal summation |
|
| 59:31 | not gonna be as great. So it, if this is spatial |
|
| 59:36 | which means at the same time in parts of the space, this would |
|
| 59:42 | temporal summation which would be in the space but over different parts of |
|
| 59:48 | So you will still see this increase you will not have as uh steep |
|
| 59:54 | a slope for this for the temporarily response. The other thing is when |
|
| 60:03 | talk about axons and action potentials. saw that there's a myelinated and they |
|
| 60:09 | action potentials and they regenerate them. so mo and dendrites are not. |
|
| 60:17 | therefore, they can be viewed sort a a little bit as leaky |
|
| 60:26 | So the information that summits here, positive currents coming in here over some |
|
| 60:32 | are actually going to leak out. if you just activated one synapse here |
|
| 60:38 | the distal dendrite, by the time signal travels down the dendrite to another |
|
| 60:47 | , let's say a few microns down dendrite, it will only be a |
|
| 60:53 | of its size or fraction of its from where it started. So you |
|
| 60:58 | have this proactive regeneration of the synaptic shaw with the EP SPS and IP |
|
| 61:07 | like you do with the action Platon , instead, they will leak out |
|
| 61:12 | this dendritic cable because it's not it's not an Axon. So now |
|
| 61:18 | cell has to have a little bit a different strategy of how to carry |
|
| 61:23 | signal, especially if you're located at distal ao dendrites, how to have |
|
| 61:30 | signal from there, enough depolarization to this guy know to fire, |
|
| 61:37 | That means you have to have really signal, really strong depolarization. So |
|
| 61:42 | if it leaks, it still reaches at the level of the selma to |
|
| 61:48 | the selma, right? Or there other strategies that sales can employ and |
|
| 61:56 | won't go into deep details about But some of the strategies is by |
|
| 62:02 | higher number of certain channels and receptors to assure a more powerful impact distally |
|
| 62:12 | could still reach the SOMA. It again is a strategy of a |
|
| 62:17 | I'm going to place voltage gated sodium channels. Here, voltage gated calcium |
|
| 62:22 | , here, I'm going to place voltage gated receptor channels in the |
|
| 62:26 | So I could still get the signal into the SOMA. And then the |
|
| 62:31 | cells go, we're going to attack SOMA because there are fewer, remember |
|
| 62:36 | they are 10 to 20% than most the circuits that will study like hippocampus |
|
| 62:41 | cortex is inhibitory cells. So they to have an impact on, |
|
| 62:45 | on the SOMA too. And so try to then attack the SOMA and |
|
| 62:50 | it the SOMA as much as they . We are out of time. |
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| 62:54 | when we come back, we'll discuss couple more concepts related to this dendritic |
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| 63:00 | and length cost that we call. see everyone here on Monday. Thank |
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| 5999:59 | |
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