| 00:02 | This is lecture 11 of neuroscience. we talked about electrical synopsis and chemical |
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| 00:08 | . We talked about the significance of synopsis as well. So several points |
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| 00:12 | points we made there some morphological differences the synoptic appearances between the exciting and |
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| 00:19 | cells. Then we spent quite a of time talking about neuro muscular |
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| 00:24 | We talked about excitatory transmission that happens between motor neuron uh and muscle |
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| 00:37 | In this case it's a skeletal muscle the release of acetylcholine causes a contraction |
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| 00:42 | the skeletal muscle. And we talked the fact that in this neuromuscular junction |
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| 00:51 | a very reliable synapse. No muscular and activation of motor neuron at the |
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| 01:00 | muscular junction activation of motor neuron causes inflated potential. That's approximately 70 million |
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| 01:11 | in size. So we're talking about . If we're talking about muscle and |
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| 01:18 | say that the resting membrane potential is minus 65 million bowls. And that |
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| 01:25 | threshold for action potential is minus 45 bowls, threshold action potential minus 45 |
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| 01:36 | bowls. Then the 70 million ball in the neuro muscular junction is always |
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| 01:43 | to reach The threshold value of -45 . And as you know that if |
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| 01:50 | reach this threshold value in this deep which is the employee potential is |
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| 01:56 | very large. So employed potential which a single Colin mediated is a very |
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| 02:04 | , deep polarization always reaches the Once these molecules are released to talk |
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| 02:12 | the releasing quantum fashion, there is 6000 of them that are being released |
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| 02:19 | uh generating this trump. And once receptor channels de polarize the muscle fibers |
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| 02:33 | you have both educated sodium and calcium takeover and generate this prolonged muscular action |
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| 02:43 | the country. That's why it's a high, highly reliable synapse. It's |
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| 02:48 | excitatory. There's no in addition in neuro muscular junction and uh we talked |
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| 02:59 | all of these different features compared to central nervous synopsis. And we'll continue |
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| 03:06 | them. But we talked about neurotransmitter with comprises neurotransmitter system. What are |
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| 03:12 | criteria for neurotransmitters? And we actually the end of our lecture here we |
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| 03:21 | about different types of neurotransmitters. So we talked about different types of neurotransmitters |
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| 03:32 | me switch to western presentation. When talked about uh several important features of |
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| 03:44 | acid transmitters. So we said that look in the central nervous system, |
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| 03:52 | brain, the brain, stone spinal . We will see that the inhibitory |
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| 04:04 | cells are widely expressed throughout different parts the brain of glycerine cells. |
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| 04:12 | so you can say that all of are Gaba. Why seen if it's |
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| 04:18 | the spinal on and when we talk excitation we have glutamate and glutamate is |
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| 04:28 | widely expressed throughout the brain and different of the brain and the spinal cord |
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| 04:38 | . But when it comes down to mean neurotransmitters, we said that that's |
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| 04:43 | the case and see the Killeen dopamine norepinephrine serotonin. They have their distinct |
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| 04:54 | typically in the brainstem areas or in frontal cortical areas here and each one |
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| 05:04 | these distinct nuclei is going to be a different mean. So the expression |
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| 05:13 | Visa means is limited to specific nuclei the support ical regions mostly. But |
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| 05:21 | doesn't mean that you have region of brain. It means that you only |
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| 05:27 | so much of neurons in that region the brain that synthesize, synthesize the |
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| 05:34 | of coal and you have it available the brain. The way you have |
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| 05:40 | available is there are diffuse and widespread from these nuclei into the brain, |
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| 05:50 | the sub cortical regions and into the . And a lot of them will |
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| 05:55 | both central supply of a certain demean also peripheral supply of a certain |
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| 06:04 | We also talked about peptides, peptides the older sister kinda remember we talked |
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| 06:10 | co sister Keenan was one of the the distinguishes between different subtypes of parameter |
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| 06:17 | cells in the hippocampus the usual CCK for CCK Nagara. Uh so what |
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| 06:25 | that mean? That means that parameter . The hippocampus which releases what kind |
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| 06:31 | neurotransmitter? It's an excitatory projection, glutamate and it expresses CCK. What |
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| 06:42 | that mean? That means that it co express. So you can co |
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| 06:48 | these molecules in different combinations or some that have glutamate, excitatory cells will |
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| 06:56 | have closest to kind in others will some out of staff. So we |
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| 07:03 | at the inter neurons in hippocampus and of them Number seven in that Diagram |
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| 07:09 | alarm cell had a stained positive for stat. So that's another neural |
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| 07:17 | That's an inhibitory cell. What does mean? That means that the cells |
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| 07:23 | release gaba as an amino acid neurotransmitter neurotransmitter can also co express co release |
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| 07:31 | amount of statin. And there are combinations of uh excited to inhibitor and |
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| 07:38 | that will be co releasing amino assets with neuro peptides. And if you |
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| 07:47 | at the neuro peptides there are differences their synthesis, transport and release. |
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| 07:54 | to the neurotransmitters. We talk about that will focus even today even |
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| 08:01 | Your transmitters are pretty much held at synapse here and in the synaptic |
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| 08:09 | That's where you have the vesicles. they get released they get re up |
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| 08:13 | back into the synaptic terminals, not the selma. If they're in the |
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| 08:18 | terminals, they get re uploaded into . So the cycling this neurotransmitter cycling |
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| 08:24 | um and and release is happening at level of synaptic terminal. But for |
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| 08:30 | peptides as you can see it's different neuro peptides have to be produced more |
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| 08:37 | less on demand for their release. what is the demand. Single action |
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| 08:42 | can cause enough of deep polarization here release neurotransmitters, Person optical but the |
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| 08:50 | action potential is not enough difficulty to the release of neuro peptides. So |
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| 08:56 | intense levels of activity and prolonged levels activity in some very engaging tasks for |
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| 09:05 | neurons neuropathy type production will be where synthesis is done at the level of |
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| 09:11 | soma off the ribosomes through the golgi . When they butt off the secretary |
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| 09:18 | and the secretary Granules are different from vesicles and the secretary Granules, they |
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| 09:25 | aim is to be transported into the terminal where they can become release of |
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| 09:32 | neurotransmitters. But they actually a lot times fuse along the external extent, |
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| 09:40 | spatially non specific release of neuro And when I say non specific is |
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| 09:45 | transmitters, it will be very specifically . They release an activity within the |
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| 09:51 | within this very small space. And you have the Secretary Granules essentially fusing |
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| 09:57 | releasing the content along the external uh here. When you don't have as |
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| 10:05 | of the spatial specificity, you know ? It's semi para crime. If |
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| 10:09 | think about like hormonal release which is or para crime and this is semi |
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| 10:15 | crime in the sense, it's not specific. Okay, so there are |
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| 10:20 | differences in synthesis transport storage and the for the release of the neuro peptides |
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| 10:28 | to the neurotransmitters prison optically we have synaptic zones we have a synaptic |
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| 10:39 | That's about 20 nanometers in in We sign optically when an action potential |
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| 10:48 | and the pre synaptic terminal, it both educated calcium channels and influx of |
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| 10:55 | is necessary to cause the secular fusion the plasma number. And of the |
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| 11:02 | and neurotransmitter release neurotransmitters will bind boston receptor channels. So these are lagging |
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| 11:11 | channels and not voltage gated. So in this case of glutamate will cause |
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| 11:17 | of sodium and post synaptic aly it cause the deep polarization this deep |
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| 11:24 | If we're talking about threshold fracture potential it says minus 55. But you |
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| 11:29 | back from this minus 45 in the nervous synapses instead of the in the |
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| 11:39 | . N. S. These are major differences. First of all you |
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| 11:44 | glutamate which is excitation and you have which is inhibition. You don't have |
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| 11:53 | at the neuro muscular junction. Another is the amplitude potential is a 70 |
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| 12:01 | ball change when glutamate gets released and causes posson optically deep polarization. This |
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| 12:09 | polarization is called excitatory post synaptic So it's abbreviated as E. |
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| 12:18 | S. V. Excited for a synaptic potential and when gaba gets released |
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| 12:25 | you'll learn about this a little bit today or next lecture. When Gaba |
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| 12:30 | released it binds to Gaba receptor channels Gaba allows for chloride to come |
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| 12:38 | So if sodium comes in you get PSP you get deep polarization posson optical |
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| 12:44 | chloride comes in its negative charge coming you get I PSP or hyper |
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| 12:50 | Okay so Gaba causes inhibitory pasta in potentials and if we're talking about this |
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| 13:00 | mira muscular junction. This and plate the size of a single E PSP |
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| 13:08 | single I PSP. It's only approximately a mil of all themselves. And |
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| 13:18 | . So if you took now this blue, this is muscle E. |
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| 13:23 | . P. In black and play tom. And let's say now you |
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| 13:32 | that I'm gonna now record from neurons this neuron gets a single synapse |
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| 13:38 | It shows a small deep polarization and it gets an inhibitory input. So |
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| 13:45 | shows a small hyper polarization and then gets a stronger inhibitor input and it |
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| 13:51 | stronger hyper polarization. And then instead one synapse activated, they activated two |
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| 13:59 | and then it gets a stronger excitatory . And maybe there's a summation and |
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| 14:05 | you reach the threshold for action potential that's when you generate an action |
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| 14:12 | So E. P. S. . S. And I. |
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| 14:16 | S. P. S. A potentials grated in the sense that they |
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| 14:23 | only half a move. Also you one excited person aps is half of |
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| 14:27 | level of change postion optical if you two synapses activated you have one more |
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| 14:36 | , Right? So you have to and activate 40 different synapses in order |
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| 14:46 | reach the threshold for action potential generation the central nervous systems analysis. So |
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| 14:55 | neuro muscular joint is very reliable action , Prison optically means to twitch of |
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| 15:00 | muscle Cns is not reliable action potential optically and activation of one synapse release |
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| 15:07 | one Mexico may mean a very small polarization. So you have the |
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| 15:13 | that's when when we talked about when we talked about the electrical |
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| 15:21 | gap junctions. Who said how important is for cells to synchronize. So |
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| 15:25 | lot of cells start communicating with each in a short period of time so |
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| 15:30 | you can reach the threshold for the potential generation. An action potential in |
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| 15:35 | cns is going to be much The action potential is all or |
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| 15:40 | So once you reach the threshold this potential, the opening of voltage gated |
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| 15:44 | channels of sodium. More sodium more sodium. This is all or |
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| 15:49 | . It has to go through the . But until you reach it it |
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| 15:53 | be half a million fold deep five million volts, 10 million volt |
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| 15:57 | polarization. This kind of a random which is basically different inputs, exciting |
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| 16:03 | inhibitory inputs coming into the cell until finally reaches the threshold for action potential |
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| 16:10 | . Okay, so plus synaptic function reception and you can see the electron |
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| 16:18 | these really nice images here. So is required or the release of neurotransmitter |
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| 16:27 | . Action potential is required. Deep . Pre synaptic people remember that action |
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| 16:33 | that gets generated by both educated sodium . Uh huh potassium channel also gets |
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| 16:43 | all the way to the external terminal that deep polarization opens both educated they're |
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| 16:53 | both educated calcium channels. So calcium is the second necessary component for the |
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| 17:01 | only with calcium influx. Ng can the secular membrane fused with the neuronal |
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| 17:10 | causing the opening of the fusion pore the release of the neurotransmitter. |
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| 17:18 | if you if you look at if you look at the simplified version |
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| 17:28 | what it takes, it takes the sneer protein complex to fuse with T |
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| 17:40 | membranes near complex. So there has be protein protein interactions are the proteins |
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| 17:47 | are dangling off the bicycle. It's possible lipid bi layer and the proteins |
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| 17:53 | are sitting in the membrane. Once comes in, there is some sense |
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| 17:59 | side the sensor size is one of is snapped to tag them on the |
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| 18:07 | that census that calcium just came in it allows that the secular protein complex |
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| 18:14 | form protein protein complex interactions with the membrane protein complex allows for the fusion |
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| 18:23 | releasing neurotransmitters. So now after the is released and wonder that once it |
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| 18:32 | being released, you see that what is you all of a sudden increase |
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| 18:39 | surface area of this pre synaptic neuron if you increase the surface area, |
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| 18:45 | if it is happening for a few while the neurotransmitter release is happening and |
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| 18:51 | it gets end of sight toast So this piece of the number. |
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| 18:55 | doesn't get thrown out, it gets . It's a valuable organ out. |
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| 19:01 | once it releases its content and once fuses the plasma number and the capacitance |
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| 19:10 | of the cell will go up because surface area will go up so momentarily |
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| 19:14 | going to be an increased probability of charge. And you can actually measure |
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| 19:20 | in capacitance during the secular release because the fusion of this additional piece of |
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| 19:26 | plasma membrane to the overall neuronal membrane is the secular member infusion. Uh |
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| 19:35 | is a interesting images from X. . Psychosis and these little dots |
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| 19:44 | You can see here the presumed calcium that we are trying to understand at |
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| 19:50 | point. You know, where are both educated sodium channels and potassium channels |
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| 19:54 | they're located? Action initial segment knows ranveer where are both educated calcium channels |
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| 20:03 | while the selva has strategy to locate pre synaptic aly because calcium is necessary |
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| 20:09 | the circular fusion. Right? So where you'll find a lot of both |
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| 20:15 | calcium channels. So we want to more about their precise location. And |
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| 20:20 | you stimulate now you can see this is the cytokine fusion for which basically |
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| 20:27 | . Ical came and fused here with membrane. And you see a |
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| 20:32 | So you're looking into the inside of testicle here. And it's very clearly |
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| 20:37 | that these vesicles and the fusion of vesicles that these pre-symptomatic active zones is |
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| 20:43 | very much aligned with this facially, much aligned with the location of both |
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| 20:50 | calcium challenges and uh this image which taken from the book called from neuron |
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| 20:57 | brain. And it's by one of probably most famous south american neuroscientists Rodolphe |
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| 21:05 | his research that showed that if you calcium sensitive dies you can visualize the |
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| 21:16 | of calcium. So let's think about for a second. We talked about |
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| 21:23 | in this course a little bit. mentioned positron emission tomography. We said |
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| 21:28 | noninvasive whole brain and shows you these maps for different activities, different parts |
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| 21:34 | the brain being active. Performing different . When you come to the experimental |
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| 21:41 | we talked about, oh you can individual neurons using infrared microscopy and if |
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| 21:49 | visualize those neurons you can jab them electrodes and do the recordings and you |
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| 21:54 | do it in vitro some of these can do in vivo also. |
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| 22:00 | But here it's calcium sensitive. So instead of imaging membrane potential instead |
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| 22:11 | imaging radioactive label isn't positive on emission you're now imaging specifically changes in calcium |
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| 22:24 | . And there are different dyes that us to track changes in calcium calcium |
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| 22:32 | dyes for calcium specific guys there are sensitive sodium specific guys potassium specific guys |
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| 22:40 | also dies. That allow us to voltage called voltage sensitive dyes. And |
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| 22:46 | can be genetically expressed. Just like indicators can be genetically expressed or they |
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| 22:52 | be applied sort of a chemical applied the brain tissue or in the whole |
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| 22:57 | . So when rodolfo llinas did these experiments we saw the spatial specificity in |
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| 23:04 | concentrations. That was an agreement with of the war that was being shown |
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| 23:09 | microscopy showing the groupings of these voltage calcium channels very closely to the neurotransmitter |
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| 23:17 | fusion sites. And you can see very discreet out of the peaks like |
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| 23:24 | peaks and here the stronger the higher calcium concentration the more red you will |
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| 23:33 | . And it showed that at a when the neuron is not releasing neurotransmitters |
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| 23:40 | have a precise spatial map of these concentrations that are aligned with the fusion |
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| 23:52 | for the vesicles. And then obviously question was well what happens when you |
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| 23:58 | cell gets d polarized and gets stimulated it releases you know it has a |
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| 24:04 | of action potentials. And so it's a lot of neurotransmitter there's a lot |
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| 24:08 | calcium influx for that neurotransmitter release to . And so if you keep repeating |
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| 24:15 | potentials prison optically you keep increasing calcium optically and you can keep releasing |
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| 24:27 | Now spatially you can see what happens there's a first of all lost some |
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| 24:33 | that special Discrete specificity that these peaks peaks had before stimulation or before the |
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| 24:41 | release. But it also shows that becomes very readily available in that whole |
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| 24:47 | . And that there is a significant up to 200 micro mall or calcium |
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| 24:53 | there by the plasma membrane, the zones to facilitate the secular release. |
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| 25:00 | that's pretty neat because these kind of show us the dynamics of islands, |
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| 25:07 | just the location of the channels. good, but what are the dynamics |
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| 25:13 | what are the real time or near time changes in the concentrations of these |
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| 25:20 | like calcium ions. And what is spatial temporal pattern of these changes? |
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| 25:28 | now on on the top right, have an image. That is a |
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| 25:33 | of the three fracture technique. That an older technique. So this came |
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| 25:39 | and uh In the 90s really uh the microscopes that were picking up. |
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| 25:45 | you would use like a fluorescent microscope to pick up the signal. But |
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| 25:53 | that, 20 or so years before people were also interested in what are |
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| 26:00 | different components in the plasma membrane and two different possible Olympic layers. So |
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| 26:06 | decided why don't we split it apart see which which components like Rodin's uh |
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| 26:13 | and associated lack of proteins, things that. Which ones are on cellular |
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| 26:18 | , which ones are inside the plastic , which ones are on both. |
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| 26:22 | they use this re fracture technique and was essentially either during the stimulation which |
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| 26:28 | you wanted to capture this particular release , you would also use this |
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| 26:32 | But even without that it would freeze small piece of the plasma membrane and |
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| 26:37 | a small needle or small object next it and tap it very junk on |
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| 26:42 | table. And that frozen membrane, you were lucky with split into two |
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| 26:48 | , the face and the face. these were anatomy. So we could |
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| 26:54 | the anatomy of the membrane components, proteins. We can understand the location |
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| 27:00 | electron microscopy which you know goes back plus years but we really couldn't visualize |
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| 27:07 | ions and the spatial temporal dynamics of ions Until 90s or so. All |
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| 27:14 | these levels of understanding the structural morphological of the sub cellular uh components as |
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| 27:22 | as the dynamics of spatial temporal dynamics important to understand the communication between |
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| 27:29 | Okay, so I think that Their and this is an electron microscope image |
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| 27:37 | shows gap junction all women. So you remember the typical distance between neurons |
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| 27:44 | the synapse which is maybe even Sometimes in typical distances 20 nm. |
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| 27:51 | here the distance in the gap junction is when we have to embrace into |
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| 27:57 | come close together and allow for these podiums from sala and Saudi to form |
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| 28:04 | functional channel. And this distance here only about 3.5 nanometers or so. |
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| 28:11 | some of these pools of gap junctions are larger, Some of them are |
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| 28:17 | . Um But we can also visualize using electron microscopy. Now another thing |
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| 28:24 | can happen in C. N. . Typically doesn't have in a normally |
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| 28:30 | neural muscular junction is a partial release a neurotransmitter. So if my task |
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| 28:36 | to pick up this water and my neurons would be doing only half of |
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| 28:45 | release of the neurotransmitter of partial Maybe that task would just be something |
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| 28:52 | this. Right? My task is . But if I don't get enough |
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| 28:57 | neurotransmitter release that means the motor commands muscle is going to get the |
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| 29:02 | So that can happen if you have dysfunction of muscular dysfunction injury and so |
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| 29:09 | in the muscles on the C. . S. It's quite problem that |
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| 29:12 | can have partial for openings and so is a typical t formation of neurotransmitter |
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| 29:21 | . They butt off early and do that gets filled with neurotransmitters they go |
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| 29:26 | hang out into this active zone where adopt so they're ready and primed. |
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| 29:34 | a whole cycle energy and other factors influence them being primed in the position |
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| 29:40 | they're just waiting for calcium. Now comes in now they confuse the membranes |
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| 29:49 | allowed with the neurotransmitter release but in instances there might not be enough |
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| 29:56 | there might not be enough calcium picked by the particular sensors. And do |
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| 30:04 | get only a partial release. So is referred to as kiss and |
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| 30:10 | So you have a partial fusion and release of the neurotransmitter. If you |
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| 30:16 | commit fully you just kiss and run you reposition yourself with this dark and |
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| 30:21 | position again. That happens in the . But typically and if you have |
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| 30:29 | reliable default realization and the necessary amount calcium in optically you will get dilation |
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| 30:40 | this fusion, pour the full release the content into the synaptic cleft. |
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| 30:50 | in uh in most of the cases will not see this in neuro muscular |
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| 30:59 | . That's another difference. The other is if you talk about what is |
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| 31:05 | is quantum release for example. There's 2000 between 2000 and 4000 settle quoting |
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| 31:15 | that get released in a single packet the neuro muscular junction. And that |
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| 31:21 | also different for different neurotransmitters. We use the seal colon example. But |
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| 31:27 | is the reason why you always have change of approximately $70 million and approximately |
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| 31:37 | a mil evolve from C. S. And you'll say what does |
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| 31:42 | mean? There's a quanta of chemicals number. And you'll see what kind |
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| 31:50 | Quanta is that between 2000 and Let's see that like one or two |
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| 31:54 | math. Right. But it's not molecules versus 4000 molecules. It's typically |
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| 32:03 | 2000 and 4000 molecules. And typically is about 70 million volts but it |
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| 32:10 | be my 60 could be 75 sometimes be 80 sometimes, but an average |
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| 32:17 | typically around 70. So that's what release means. Now once again, |
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| 32:25 | in the vesicles fuse this and it released and we go back in the |
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| 32:30 | . N. S. It doesn't wasted, it gets recycled in the |
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| 32:35 | owes, it gets marked as a of the membrane that is a vest |
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| 32:40 | that has released, its content gets with Claritin gets recognized as such with |
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| 32:47 | help of a teepee gets loaded up a proton age plus a proton gradient |
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| 32:54 | a lot of neurotransmitters into the loads them up, get them ready |
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| 33:00 | prime and release and in some cases may get sent back for more significant |
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| 33:08 | and restructuring at the level of the so early Anderson we get engulfed back |
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| 33:15 | Orlando sound and then butt off again a new bicycle. So it's all |
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| 33:21 | at the level of the uh most this cycling is happening at the at |
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| 33:27 | synapse level. Let's go. Okay actually let's talk about a couple of |
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| 33:36 | , let's talk about E. B. We talked about potential and |
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| 33:43 | gonna mark a few. Are there here about potential. Cool so the |
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| 33:54 | place potential is when you have two civil coding molecules have to bind acetylcholine |
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| 34:05 | that will allow for the influx of do you. And for the e |
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| 34:13 | of potassium. So these are ligand or receptor channels but they're not like |
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| 34:21 | ones that we talked about, voltage sodium channels. Or specific selected for |
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| 34:25 | selected for potassium channels selected for These allow for the influx of sodium |
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| 34:31 | that's where you get the initial deep of the employee potential and for the |
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| 34:38 | of potassium. So a lot of gated uh channels will allow for the |
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| 34:46 | of more than one ions in the . N. S. Mhm. |
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| 34:56 | we're talking about excitation or inhibition. for excitation, okay this is our |
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| 35:12 | channel Glutamate receptor channel glutamate has to for it to it. It will |
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| 35:18 | allow for the influx of sodium and of potassium and glutamate will be responsible |
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| 35:27 | generating E. P. S. . S. Post synaptic early excitatory |
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| 35:33 | synaptic potentials. Now when gaba binds this is a simplified version of this |
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| 35:41 | a deep polarization through sodium channel. you will learn everything that you wanted |
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| 35:46 | know more about to mutter chick neural and MDM from kind of centers and |
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| 35:53 | I'll flux through them. But this the PSP. And if Gaba binds |
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| 36:00 | receptor channel that allows for the influx chloride and chloride negative charge going in |
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| 36:12 | I. P. S. You give me color pounds. I |
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| 36:20 | dangerous and then E. P. . P. So I PS PS |
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| 36:26 | charge build up and E. S. B. Would be obviously |
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| 36:30 | a positive charge build up. So the TPP is only excitatory so you |
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| 36:44 | put just excited to it. So somebody potential is just excited tori there's |
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| 36:53 | inhibition neuro muscular junction and CMS. have inhibition and excitation. So does |
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| 37:00 | mean that parameter cell can have Yes from very early on I said |
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| 37:06 | neurons Maybe receiving 2000 inhibitory inputs, few 100,000 excitatory inputs and they integrate |
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| 37:16 | of that information. So the cns will have excitation and inhibition but not |
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| 37:23 | the neuro muscular junction. There is on the tropic signaling. What we |
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| 37:33 | in the tropics signaling is the chemical ligand binds should receptor channel and ions |
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| 37:41 | through that receptor channel. This is a tropic. It conducts ions through |
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| 37:47 | receptor channel. It's a channel but also metabolic tropic or indirect signaling in |
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| 37:55 | case a neurotransmitter doesn't open the It's not a channel. Instead it's |
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| 38:04 | to G protein complex. So they're to as G protein coupled receptors or |
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| 38:10 | P C R. S. G coupled receptors receptors that are coupled to |
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| 38:16 | protein complex when neurotransmitter binds to that catalyze is activist. The G protein |
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| 38:25 | and different subunits of this complex can their effects on the neighboring protein channels |
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| 38:34 | downstream cellular defectors enzymes and secondary messengers even transcription doctors here it's really powerful |
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| 38:46 | with some delay. So if you about neurons that produce fast action |
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| 38:52 | muscles produce long action potentials. So slowest or the fastest. And neurons |
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| 38:58 | the cns glia don't produce action We communicate through calcium waves. Sometimes |
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| 39:08 | waves but no action potential. So temporal scale at which glia communicates and |
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| 39:15 | information in the brain and the processes in a much slower right down to |
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| 39:21 | control and cytokine release, which is slower compared to one or two millisecond |
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| 39:27 | potential that urine is produced. So if you bind you release neurotransmitter pre |
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| 39:34 | aly and that neurotransmitter has to travel post synaptic side. It has to |
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| 39:42 | to the channel receptor channel. This a little bit of time. It's |
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| 39:49 | action potential is 1 to 2 This synoptic release travel binding. It's |
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| 39:58 | synaptic delay between when the stimulus start the action potential started and when there |
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| 40:03 | a response. Post synaptic lee, you record the response in the |
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| 40:08 | person optically synaptic delay can be few to 20 milliseconds, depends on the |
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| 40:16 | , depends on certain specific subtypes of and such the synapses sizes distances and |
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| 40:23 | on. So uh well you have delay here. This is different from |
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| 40:33 | electrical gap junctions. There's no delay there's nothing traveling across the synapse, |
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| 40:40 | have the spread of an eye on small molecule or charge from one neuron |
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| 40:46 | to another neuron through these open electrical junction channels. So this synaptic thing |
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| 40:56 | a little bit of delay. Chemical transmission has this synaptic delay. Electrical |
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| 41:02 | doesn't have any delay. But I a tropic. When the ligand binds |
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| 41:09 | this receptor channel opens this receptor it's fast maneuver tropic. You have |
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| 41:18 | catalyze the G protein complex, that has to move into adjacent numbering space |
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| 41:26 | for for late may be influencing adjacent channel so they can regulate nearby channels |
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| 41:33 | not directly to bind the neurotransmitters to . But through the G protein complexes |
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| 41:38 | might be 2050 102 100 millisecond So the tropics synaptic transmission again is |
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| 41:48 | slower mode of operation. But it's a different mode of operation because it |
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| 41:54 | influence the enzymes the secondary messengers and the transcription factors in the nuclei of |
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| 42:01 | post synaptic cells. And once you that, once you touch upon the |
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| 42:07 | machinery of the cell and transcription factors can exert longer lasting effects. And |
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| 42:14 | post synaptic cells different effects a neurotransmitter effect than the same cell. Different |
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| 42:22 | in different cells. So we'll come to this maybe. But we already |
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| 42:27 | that how acetylcholine can cause contraction of muscles and how it acts the nicotine |
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| 42:34 | receptors and then the cardiac muscle it down or reduces the contraction of the |
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| 42:40 | because it's acting through different dominant by acetylcholine receptor which is metabolic tropic. |
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| 42:47 | receptor. Oh um different effect in same cell. Same neurotransmitter because you |
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| 42:55 | have two different subtypes of miserable tropic that will exert opposing actions but they |
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| 43:03 | to the same chemical. So but will be a little bit more clear |
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| 43:08 | we talk about norepinephrine, alpha and receptors. Okay now we'll talk about |
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| 43:14 | civil coding and you'll know a lot acetylcholine and you'll be responsible for knowing |
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| 43:23 | about a civil killeen like its synthesis breakdown and some other things that will |
|
| 43:32 | . So Macedo Colleen is in motor . We talked about this neuro muscular |
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| 43:39 | all P. N. S. Raonic and parasympathetic nerve endings. Siegel |
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| 43:47 | is in the brain and the cns talk about there's a limited number of |
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| 43:53 | in the nucleus that's in the scene will express acetylcholine and diffuse it through |
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| 44:00 | projections widely throughout the brain. Acetylcholine synthesized when and Colleen come and chat |
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| 44:12 | . So for the exam if you decide for chad just calling the seal |
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| 44:17 | you're in good shape on the synthesis they chat together. Pharmacy locally cecil |
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| 44:24 | was loaded up into the vesicles it released and it will bind in the |
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| 44:30 | . N. S. To academic receptor channels en masse sarinic metabolic tropic |
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| 44:41 | receptors in the C. N. . In the neuro muscular junction you |
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| 44:47 | have nicotine acetylcholine receptors and then in C. N. S. You |
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| 44:54 | nicotine acetylcholine receptors and you have mascara , acetylcholine receptors, those of medical |
|
| 45:08 | . Maybe this is a good Point to talk about. This. |
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| 45:13 | is an endogenous molecule produced in our and our bodies. Uh and we're |
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| 45:21 | about C. N. S. course in this case and it will |
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| 45:25 | an academic and this is a receptor . This is a couple of something |
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| 45:34 | which comes from tobacco is an agonist also bind some nicotine acetylcholine receptors. |
|
| 45:45 | nicotine nick is after nicotine. Nick will have their own agonist musk |
|
| 45:54 | . Another molecule. These are exogenous , societal Colleen and then exogenous or |
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| 46:04 | because we don't produce nicotine. Tobacco produce nicotine uh agonist something that opens |
|
| 46:13 | channel agonist binds the new pathetic It opens up the channel antagonists if |
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| 46:22 | binds to that receptor causes the closure the channel. So each one has |
|
| 46:29 | own distinct antagonists curare which comes from little poison frogs in south America that's |
|
| 46:39 | used for poisonous darts by some indigenous for hunting in the amazon and atropine |
|
| 46:48 | . Some of these can be exogenous coming from other creatures animals, |
|
| 46:57 | plants like nicotine, other exogenous could human synthesized lab synthesized chemicals right? |
|
| 47:07 | atropine and Ferrari will have their distinct block silicone receptor agonists will encourage the |
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| 47:19 | of G protein complex and antagonists will the catalysis but will stop it from |
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| 47:25 | catalyzed. In this case formidable tropic . So settle coding receptors once they |
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| 47:32 | once once they get bound up by code in in the cns we'll talk |
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| 47:37 | their functions. You'll notice that they slightly opposing functions from the spies that |
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| 47:44 | control of excitability, deep polarization and post synaptic neurons. Once acetylcholine is |
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| 47:52 | in the synapse and binds to the , we also talked about it. |
|
| 47:56 | very important that neurotransmitter systems. They a way to degrade neurotransmitters or they |
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| 48:03 | a way to transport them back into pre synaptic terminals and they have a |
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| 48:08 | to re upload them back into vesicles they don't get wasted. The chemicals |
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| 48:12 | get wasted and they also don't bind and stay bound up to these receptors |
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| 48:18 | they bind to these receptors, activate and they get released. So then |
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| 48:22 | get broken down by Seattle colonists. okay settle colonists race choose it up |
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| 48:31 | to see the castle and choline. . Acetic acid and Colin Colin gets |
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| 48:39 | actually co transported with sodium into the synaptic terminals, binds again, finds |
|
| 48:48 | little coup way they chat together form little Colin gets reloaded into the vessel |
|
| 48:56 | in the first portion of this course talked about Alzheimer's disease when we talked |
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| 49:00 | Alzheimer's disease. We mostly focused on pathological hallmarks of Alzheimer's disease and on |
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| 49:07 | cellular level or circuit level. We about how you have your own february |
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| 49:13 | inside the south one of the pathologies the south, we can have dementia |
|
| 49:20 | data amyloid plaque formation. We also that on a gross anatomical level and |
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| 49:28 | the severe stages of Alzheimer's disease, will have a significant loss of brain |
|
| 49:34 | . So shrinkage, especially in the matter of the brain. We talked |
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| 49:41 | the onset of the disease of see by age that it is an |
|
| 49:47 | 50 and plus is more likely when person may develop or show Alzheimer's |
|
| 49:55 | Symptomology. We talked about symptoms, is, we talked about memory impairment |
|
| 50:02 | memory mostly because this is the first that comes to mind. But as |
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| 50:06 | know, as the disease progresses, is memory and memory is not the |
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| 50:11 | thing. Those plaques or the tangles be affecting. Different neuronal circuits responsible |
|
| 50:17 | different functions. Right down to the functions of your of your brain and |
|
| 50:22 | body losing control and leading to to essentially. We didn't talk about |
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| 50:32 | We didn't talk about medications today, talk about therapy very briefly because the |
|
| 50:40 | Alzheimer's medications that are out on the , overwhelming majority of them are cathedral |
|
| 50:47 | or ace inhibitors. So you will some commercials for for drugs on TV |
|
| 50:55 | you will even here in some commercials diabetes medication or something like that if |
|
| 51:01 | are on since, which is uh Esther is inhibitors or as we |
|
| 51:08 | a single column nestor is pollen Esther just an abbreviation. So why is |
|
| 51:16 | the case? And why is it a cyclical industry? So one of |
|
| 51:21 | other features of Alzheimer's disease is loss Colin ergic neurons. Number said that |
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| 51:28 | Colin ergic neurons which are means are in a limited subset, a few |
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| 51:34 | of neurons in a specific nuclei in brain stem or the basal forebrain. |
|
| 51:44 | what that means is that in Alzheimer's is a significant loss of Colin ergic |
|
| 51:51 | of a civil coding neurons. They're . And what this medication does is |
|
| 51:59 | prolongs so if neurons a dime and only a few of them left that |
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| 52:04 | acetylcholine when you block the signal call increase and prolong the by availability, |
|
| 52:13 | of this molecule so it can keep to the receptors. And I always |
|
| 52:19 | this up is that this is again . Uh part of the Alzheimer's therapy |
|
| 52:27 | that is not working too. There's cure for Alzheimer's disease. You can |
|
| 52:33 | slow down the progression of the And now what happens if you lose |
|
| 52:44 | of this little cold? Is this even useful? Not really. |
|
| 52:55 | So I put this on you did you see what the slide was |
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| 53:07 | neural pharmacology, designing new neuro pharmacological for severe untreatable incurable neurological disorders. |
|
| 53:23 | could be one of your goals for future. And either way that you |
|
| 53:28 | it through many different diseases that are there and many different professions. Uh |
|
| 53:37 | this is why I always say what's quite often I get students to |
|
| 53:41 | , oh well just feed them acetylcholine if there is no single Colin |
|
| 53:48 | just feed them, feed them and Colin and we can kind of laugh |
|
| 53:53 | it and show it off. It's okay well what if we had some |
|
| 53:58 | of thing that we could give a choline and and have some sort of |
|
| 54:03 | spatially specific release of that choline to the neurons in the brain. If |
|
| 54:13 | if we like produce some sort of smart nerd or drug that spatially specific |
|
| 54:18 | can still communicate through the same areas subtle color neurons would be expressed. |
|
| 54:25 | about receptors, receptors are not going necessarily. You actually first lose acetylcholine |
|
| 54:35 | then once there's no single polling then these receptors have no no rather |
|
| 54:41 | reason a lot of times sometimes the that will be responsive to several chemicals |
|
| 54:46 | the brain so they may not go . But this is another another approach |
|
| 54:51 | could be done. But this is one target and this is not the |
|
| 54:57 | dysfunction of Seattle colon is not the dysfunction and just call energetic synapse and |
|
| 55:02 | a single column esters, there's only target when you talk about drug targets |
|
| 55:07 | pharmacological targets? You want to start about multiple targets. What are the |
|
| 55:13 | multiple targets receptors or targets precursor molecules targets replacement of this molecule in the |
|
| 55:24 | . Um What about injections specific pump that you know? I don't know |
|
| 55:31 | that's been really explored but that's something want you guys to think about because |
|
| 55:36 | about again how to come up with better Alzheimer's drug in the future it |
|
| 55:42 | be very highly effective and could be delivered. You had a question what |
|
| 55:51 | if it's too much? So I if you use the log too little |
|
| 56:05 | have Alzheimer's and you have some symptomology memory loss and if you have a |
|
| 56:10 | of people maybe you have a great memory and the fruit memory. Um |
|
| 56:19 | is what we all are these new and the connections between them and the |
|
| 56:26 | . It's like a ministro knee soup you move one piece of the soup |
|
| 56:33 | the other pieces also move around. release one chemical and can influence the |
|
| 56:38 | of other chemicals and each one of is a slightly different than Australians or |
|
| 56:44 | choose your foe. Different different foe uh different chemicals are kind of all |
|
| 56:53 | similar and we all express very similar but that's what gives us the ability |
|
| 56:58 | be different also is potentially the number receptors. We have the number of |
|
| 57:05 | that produce certain chemical over the other . The connectivity to certain parts of |
|
| 57:10 | brain because there are norepinephrine is tied also to fight or flight flight response |
|
| 57:20 | tied to fear response. It means afraid of something. So it's you |
|
| 57:26 | , it's a chain reaction of that set off between these different chemicals under |
|
| 57:34 | . And uh there are probably studies a single Coleman gets over expressed and |
|
| 57:40 | look at animal behavior, you probably do it in humans. Uh but |
|
| 57:48 | the target perspective, you know, other things, there's inflammation in the |
|
| 57:53 | , there is what we call excited , there's too much calcium, it's |
|
| 57:58 | much glutamate neurons start dying. We going through apoptosis programs all day. |
|
| 58:06 | is uh abnormal immune and sido con in the brain that's all involved and |
|
| 58:14 | all be contributing to early stages to loss of these culinary arts. That's |
|
| 58:18 | I said the targets could be In fact, one of the medications |
|
| 58:22 | glutamate signaling. That's on the But it's just quite disappointing that there |
|
| 58:29 | that much on the market that's affected apart from the local Minister racism, |
|
| 58:34 | are affected at slowing down the progression the disease. Great questions keep thinking |
|
| 58:42 | it. All of these neurotransmitters, that's what makes us unique and the |
|
| 58:47 | what makes us unique. And sometimes can develop a very strong connection to |
|
| 58:52 | fear centers and they're fearful. And the phone. Ologists will say you |
|
| 58:56 | a bump here on the head that you are fearful right? But that |
|
| 59:01 | kind of the way we we went in you know in the 18th 19th |
|
| 59:06 | but but we now know that this happening internally inside not as bumps on |
|
| 59:13 | outside of the skull. Um So I'm assuming they're like para symptomatic |
|
| 59:27 | Ah I don't know well the peripheral versus central supply. Yeah so some |
|
| 59:35 | these molecules again and they will uh have the peripheral supply. You'll have |
|
| 59:41 | of them that's more preserved in the because it's uh it's a more central |
|
| 59:49 | system disorder. So the plaques for are very likely to form in the |
|
| 59:54 | lobe and from there they migrate. don't typically see the plaques and the |
|
| 60:05 | cord and I don't know the exact . I think it's really advanced severe |
|
| 60:10 | . You may but it impacts the impacts the C. N. |
|
| 60:15 | So some of this pathology that we're about an inflammation that's happening. It's |
|
| 60:20 | more of the central Colin ergic neurons that's what's affecting your cognitive functions |
|
| 60:25 | But there's also eventually with severe stages be motor impairment to people have difficulty |
|
| 60:34 | , even swallowing and that's what leads eventual death to there's loss of senses |
|
| 60:41 | attrition and loss of census. You loss of smell, loss of |
|
| 60:47 | Everything is lost typically And taste apart sweet. It's the last taste that |
|
| 60:55 | patients uh can perceive, I had student actually that was working with Alzheimer's |
|
| 61:02 | last year and this class and shared interesting detail how caretakers have learned that |
|
| 61:12 | you lose the taste except for it's really just about the texture and |
|
| 61:17 | they would put sugar in everything. sugar in the sauce is sugar and |
|
| 61:22 | just to help the patients perceive, know, perceive the taste, which |
|
| 61:27 | a sweet taste. So and the with it. So these are all |
|
| 61:32 | good questions now. Uh maybe part the answer to your question also will |
|
| 61:39 | in this slide which I'll spend a bit of time talking about. So |
|
| 61:43 | have this poisoning of neurotransmitter release. in your book of special interest |
|
| 61:49 | spider snakes and you you have to a lot with it because we are |
|
| 61:56 | by bacteria, spiders, snakes and clostridium botulinum, for example, produces |
|
| 62:06 | toxins and produces a disease called So if you have old canned |
|
| 62:15 | you can get poisoned with botulinum You're vomiting poisoning can be toxic sometimes |
|
| 62:25 | deadly depending on the amount of the is being consumed. But you're also |
|
| 62:33 | to a Botox party where the same toxins are being carefully injected around the |
|
| 62:44 | on the face typically. That has . Wrinkles form because we move the |
|
| 62:50 | muscles move the skin with age, skin stretches from the wrinkles. So |
|
| 62:57 | you get Botox objections what Botox It actually prevents the pseudo code and |
|
| 63:04 | binding in the civil code and And people after they get injections and |
|
| 63:08 | that have difficulty speaking sometimes because their are not as agile and not being |
|
| 63:15 | . And if you don't move the it smoothes out the skin a little |
|
| 63:18 | because the look of of youth back a little bit. So that's really |
|
| 63:24 | and interesting. So you have the , they produce the bacteria that produce |
|
| 63:31 | toxins. Okay and then you have toxin. You isolate that toxin and |
|
| 63:37 | use it for beauty purposes and the party friday get champagne. Never tried |
|
| 63:44 | fillers is different. So when people fillers fillers just stuff your different parts |
|
| 63:52 | your body with with some gelatinous like basically it's different from both toxin injections |
|
| 64:00 | is a toxin. Another thing is is an FDA approved Botox injections to |
|
| 64:07 | migrants migrants is not headaches, migrants a neurological disorder. And there's an |
|
| 64:14 | approved protocol for injections to treat migrants botulinum toxin. So here's an example |
|
| 64:23 | nature human for beauty purposes and then going in to get themselves beautified and |
|
| 64:33 | with migrants saying I was not feeling migraine as much and they're like wait |
|
| 64:37 | second also is a d a approved . Um Now black widow venom is |
|
| 64:48 | spider can target acetylcholine release. Also like Taiwanese cabra will produce alpha bungalow |
|
| 64:58 | and it can target posse synaptic acetylcholine so you can influence with these toxins |
|
| 65:04 | release or in this case the fusion Botox or you can influence the posse |
|
| 65:10 | receptor, blocker synaptic receptor, activate pot synaptic receptor. These are again |
|
| 65:18 | bacteria, microorganisms, spider snakes and and humans us also emphasize organophosphates and |
|
| 65:31 | are used for peaceful purposes for some applications. Organophosphate states are actually a |
|
| 65:44 | colonist or ace inhibitors. Organophosphates are gasses so they're used for biological chemical |
|
| 65:59 | essentially for illegal purposes. So good in the lab study stuff, they |
|
| 66:04 | bad things and then those bad things up with bad guys and there's bad |
|
| 66:09 | , they have it forever. They're chased around. So um there are |
|
| 66:14 | attacks with nerve gasses and and Japan subway station was a famous attack in |
|
| 66:24 | nineties. Russians used it when Chechens over the theater in Moscow to poison |
|
| 66:32 | and their own people. Syrians used to poison their own people. So |
|
| 66:38 | is still something that's prevalent and persistent organophosphates will kill you but they will |
|
| 66:45 | kill you by. Typically we have single common receptors also that are expressed |
|
| 66:52 | in the body. We talked about die frying expresses acetylcholine and so exposure |
|
| 66:59 | organophosphates will increase acetylcholine, there'll be much acetylcholine what can happen from too |
|
| 67:07 | Acetylcholine, your muscle starts contracting so that it locks up in this constant |
|
| 67:14 | called the tetanus. You cannot And if it cannot relax, you |
|
| 67:18 | no longer breathe. You can no take breath. It just locked up |
|
| 67:23 | a cramp and it shuts down your . And this leads to death with |
|
| 67:30 | to nerve Galaxies. So this partly your question where the fact if it's |
|
| 67:38 | , you have to think about Again. We talked about blood brain |
|
| 67:41 | . You take these Alzheimer's medications to them as pills. That means there |
|
| 67:46 | going to be a systemic effect too that medication, right? And you |
|
| 67:52 | to weigh the benefits or the effectivity it crossing into the brain and the |
|
| 67:57 | of it by availability and all of things. But uh yeah, too |
|
| 68:02 | of a good thing can be a thing. So too much of muscle |
|
| 68:06 | leads to titanic block up of the . Too much of the neuronal stimulation |
|
| 68:11 | little clothing can also have bad Um so it's regulated and it's balanced |
|
| 68:19 | if it is imbalanced, it's typically with neurological disorders, Seal Colin with |
|
| 68:25 | disease. Do opening with Parkinson's serotonin with depression and anxiety and so |
|
| 68:34 | . All right. I'm gonna end today. Thank you very much. |
|
| 68:38 | I will see everyone on |
|
