| 00:01 | So again, we're talking about Colin your pharmacology endogenous on exogenous agonists, |
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| 00:13 | and dajun Issa's anything produced inside the exogenous. Anything that is produced outside |
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| 00:19 | body. Um, thank you. it's outside. The body can be |
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| 00:28 | by plants. Uh, nicotine, comes from tobacco or from animals cure |
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| 00:37 | , which comes from little poison Okay, so those air endogenous and |
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| 00:44 | distinctions now, we discussed Cata Cola and we discussed, um, the |
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| 00:52 | pathway for catacomb ian production, and review it again, and I'll place |
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| 00:57 | within broader context of neuroscience and brain as a whole. And there was |
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| 01:05 | question about Monami and, uh, and NACE inhibitors. We talked |
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| 01:13 | uh, illicit drug actions and also drug effects on these pathways and the |
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| 01:20 | transmission pathways which a lot of times to do with either blocking re |
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| 01:25 | Well, they knew our transmitter or the degradation of that neurotransmitter, even |
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| 01:31 | synaptic cleft, or once it has re uptake and again. So this |
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| 01:37 | would be, um, and enzyme would break down Mona Means and |
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| 01:45 | uh, Mona Mona's inhibitors and are centrally prolonging. Now the availability of |
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| 01:53 | means inside the pre synaptic side and serve as anti depressant medications molecules as |
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| 02:04 | . I mean acid neurotransmitter letters, and GABA and will come back to |
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| 02:09 | and lie seen. So glutamate is . Torrey licenses inhibitor in the spinal |
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| 02:15 | and Gabby's inhibitor in the C. s. But in the CNS, |
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| 02:19 | well, as you'll see is also factor for activating and excited to glutamate |
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| 02:26 | . And we talked about Glitter made converted into Gabba through the time of |
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| 02:31 | , Kobach, Selous and again we'll a little bit more of these slides |
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| 02:35 | the broader context, off limits signaling the synapse. Then we discussed our |
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| 02:42 | start to allergic signaling, and we the roll off Prozac medications and blocking |
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| 02:49 | serotonin re uptake, which will again by availability. In the synopsis, |
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| 02:55 | then proceeded to talk about the and we described the system in |
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| 03:00 | if you have these classical vesicles neurotransmitters are gabba or glutamate, then these |
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| 03:10 | , upon great release of these increased heightened activity of this neurotransmitter release |
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| 03:17 | the heightened Boston Applicant activity and the will be produced on demand. |
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| 03:23 | they will their lipid soluble and is to this entire grade signaling from prison |
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| 03:30 | to pass an African this retrograde By then, the cannabinoids that will |
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| 03:35 | the CB one or cannabinoid receptor one precent optical, which is coupled to |
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| 03:40 | protein, and this Jeep Odeon activation reduce and control the opening off the |
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| 03:49 | channel. So actually closed this calcium , reduce of the secular release so |
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| 03:55 | polarization and do suppression of an ambition inhibitory synapses to deplore ization do Suppression |
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| 04:00 | expectation will review again in just a slides. He's endogenous molecules and undermine |
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| 04:07 | to our abdominal glycerol to a And this is exogenous molecule Delta nine |
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| 04:14 | Retrograde signaling also applies not just under , but also to the gas is |
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| 04:20 | it's just not just oxide and carbon . Studying these neurotransmitters and expression of |
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| 04:27 | neurotransmitters we're reviewing here to techniques. of them is immunities to chemistry and |
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| 04:33 | one and then see to hybridization you know, history, chemistry, |
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| 04:38 | you actually identify molecule of interest Let's say you have in your transmitter |
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| 04:42 | interest that you have identified. Now are maybe isolated that transmitter from from |
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| 04:49 | mouse from a rat you injected into animal like a rabbit rabbit will react |
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| 04:55 | will produce antibodies to this neurotransmitter, you can extract these antibodies and antibodies |
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| 05:01 | designed essentially to buy. And the neurotransmitter that you injected to create these |
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| 05:07 | and antibodies will be tagged with visible most of the time these visible markers |
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| 05:14 | fluorescent markers, and you're going to able to apply these antibodies on brain |
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| 05:20 | sections on brain tissues, and you're to use a little bit off detergents |
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| 05:25 | Trident eggs doing immuno history chemistry labeling break down the membranes, especially if |
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| 05:31 | molecule or your neurotransmitter of interest is . Interest valuable Inside the plasma membrane |
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| 05:37 | may use. Antibodies for the receptors located on trans membrane, and antibodies |
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| 05:44 | bind the extra cellular part of these . But if you're using antibodies, |
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| 05:48 | need to penetrate into the neurons into south, and you're gonna wash a |
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| 05:54 | bit with some detergents in order for antibodies to penetrate into the south and |
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| 06:00 | the antibodies that will bind to the will remain and the cells that are |
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| 06:07 | for those neurotransmitters and other antibodies will find these neurotransmitters in the adjacent cells |
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| 06:13 | Jason Networks, and therefore you will see a signal or stain from that |
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| 06:18 | self. So this is immune. has the chemistry because you're essentially using |
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| 06:22 | immune response, uh, rather to respond to this foreign injected candidate molecule |
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| 06:30 | neurotransmitter on the right. You haven't hybridization where now we know the |
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| 06:39 | the genomic code, and you can a certain sequence off new click |
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| 06:46 | That is essentially, um, designed you to bind a complementary strand of |
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| 06:55 | RNA that would be find in these , these brain slices. So you |
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| 07:01 | this, uh, designed radioactively labeled . It has a very specific |
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| 07:08 | I call it a sophisticated genetic Velcro sophisticated sequence off nuclear acids That has |
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| 07:16 | be exact and complementary to strand of RNA A. That would be coding |
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| 07:22 | would be coding for a molecule that be coding for a protein that would |
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| 07:27 | coding for something in the south and the South that have that messenger in |
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| 07:33 | will now expose this die, which revealed using the radioactive label material. |
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| 07:40 | two different techniques and this technique you're antibodies and directing antibodies to find that |
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| 07:48 | and expose the south of contain that , using antibodies that have been tagged |
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| 07:54 | fluorescence and then see the hybridization you're strands off radioactively labeled sequences of nucleic |
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| 08:04 | and targeting some Strand's complementary strands of and exposed using radioactive label. So |
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| 08:13 | will accomplish the same and thus far revealing the South that are expressing neurotransmitter |
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| 08:23 | . Then this final technique that we and we actually mentioned it at the |
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| 08:29 | beginning, because if you think about this technique off mimic re your transmitter |
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| 08:37 | raise that if you stimulate this present pick ax on on. You think |
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| 08:42 | this prison after Jackson releases glutamate, you will record a posson optic deep |
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| 08:48 | . So now, if you were take that glutamate and put the glutamate |
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| 08:53 | the Pipat and instead of releasing glutamate stimulating the axon and causing the release |
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| 09:00 | glutamate here onto the done right now , you actually have glutamate in this |
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| 09:06 | pot. That and you apply or spill a little bit of this glutamate |
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| 09:13 | the same area on the dem drive passing electrical car from by applying a |
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| 09:18 | bit of pressure so this would be glutamate, and then Boston optically you |
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| 09:23 | to record again. I'm excited to equally. So, uh, that |
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| 09:28 | correspond. Same way thio activating an Terry with a lethargic synapse. So |
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| 09:37 | I brought up the Lowy because on low, we did that in a |
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| 09:42 | crude way. When he discovered chemical transmission, he collected the fluid from |
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| 09:48 | stimulated heart. So he stimulated. of a single act song from a |
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| 09:53 | , he stimulated vagus nerve, and collected the fluid. And then he |
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| 09:58 | the fluid onto a naive heart that not stimulated. And so he showed |
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| 10:04 | that fluid would have the same effect the vagus nerve. And finally, |
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| 10:11 | lost section, we started discussing on neurotransmitters, and I put some additional |
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| 10:18 | for you to look up in the folder. The supporting materials about engaging |
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| 10:24 | and the point is that if you such techniques like applying or puffing a |
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| 10:32 | bit of liquid and very small micro on this neuron. What is likely |
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| 10:39 | happen is that this liquid and that , that chemical that you may have |
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| 10:46 | the solution will diffuse. And so diffusion, your micro pie path, |
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| 10:52 | be only one micro meter in diameter the opening at the tip. But |
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| 10:59 | diffusion off that chemical might cover quite large area, maybe 10 maybe |
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| 11:05 | maybe 20 micrometers in diameter, depending the pressure and depending on what |
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| 11:11 | What experimental solution is surrounding the So then it becomes very difficult to |
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| 11:18 | single synapses because glutamate diffusing in this may activate more than one synapse. |
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| 11:25 | what we discussed about neural transmitter caging engaging, is that when you use |
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| 11:32 | engaging, you use very sophisticated fast . And these lasers break the cage |
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| 11:41 | release neurotransmitters and very, very small areas equating thio barely just one synapse |
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| 11:50 | space. And so, if you at what is basically, um, |
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| 11:56 | best methodology to activate a single synapse doing uncaged in of neurotransmitters. Using |
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| 12:04 | lies is using very, uh, lasers confined to very, very small |
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| 12:13 | area corresponding to just a single And so again, if you are |
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| 12:19 | electrophysiology buff, if you are an , if you are in image |
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| 12:28 | If you are in laser applications, thio biology, uh, then engaging |
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| 12:37 | transmitter, says ISA, technique that would like to look into as one |
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| 12:41 | the most precise techniques that you can different synapses and food. Four |
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| 12:48 | three dimensions in space and the fourth being in time on this activation can |
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| 12:55 | very, very fast. And if are really physics or laser Boston, |
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| 13:02 | know that the world is moving toward Cento and has moved into the bento |
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| 13:07 | Blazers. That's how fast the lasers getting now these little blue blitzes of |
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| 13:15 | of light. Okay, so this an example of an embryo, and |
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| 13:20 | is an example where I would like discuss it. This is a sustaining |
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| 13:24 | could take a whole embryo, and this case, it's showing expression off |
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| 13:29 | be, which is Tyrus and Kinesis two receptor. Uh, and it's |
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| 13:37 | is showing is everywhere that you see staining this dark blue. You have |
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| 13:42 | disdain for this truck be, and showing that it has very high expression |
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| 13:51 | in the central nervous system. Pretty expression here, going into the brainstem |
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| 13:56 | then the spinal cord a little bit in the periphery, but not as |
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| 14:01 | . And this is a 14 a day mouse embryo. What's important is |
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| 14:06 | techniques like communal history, chemistry and hybridization not only allow you to visualize |
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| 14:12 | networks of cells and where the cells expressed in the whole animal, the |
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| 14:18 | brain or the whole embryo, but the fact that a lot of these |
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| 14:25 | parents change with maturation, where some these neurotransmitter molecules and the receptors might |
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| 14:36 | expressed to hire a lesser extent, changes during maturation. And it can |
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| 14:44 | change during the agent processes. So not just that, in a way |
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| 14:49 | showing you a static expression level of molecules. But if you look at |
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| 14:55 | over time like over the development over , you will see that these molecules |
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| 15:00 | the expression patterns are not static, static. And either the volume or |
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| 15:06 | even the spatial patterns of expression are . And embryonic prenatal, Marshall's Post |
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| 15:15 | um, circuits. So we talked some very important things we described last |
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| 15:25 | . The fact that e p s and a single CNS synapse produces very |
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| 15:31 | e p s ps on the order half a mil a vault thio a |
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| 15:36 | million volts because you need to activate synapses in order Thio reach the threshold |
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| 15:43 | action, potential generation and so on left. What you see is you |
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| 15:49 | an action potential arriving at a dendrite recording in the soma that shows a |
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| 15:55 | , deep polarization in the form of Terry pasta Napoli potential. Now, |
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| 16:00 | you have three of this synopsis that located close to each other in |
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| 16:06 | you may achieve what is called spatial where the inputs excited to the inputs |
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| 16:13 | P s PS will now summit in . And if it happens so at |
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| 16:18 | same time, you will get a larger pasta synaptic deep polarization. It |
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| 16:24 | record much larger posson optical polarization potentially enough to even reach the threshold for |
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| 16:30 | potential generation. The other way in you can some eight and build up |
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| 16:35 | excited Torrey D polarizing uh, signal by temporarily some mating. So this |
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| 16:45 | , instead of having three accents that firing at the same time and are |
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| 16:50 | close to each other in this this axon will produce three consecutive action |
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| 16:55 | . Papa, Papa, Papa. call them trains of action potentials because |
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| 16:59 | sounds like a like a train going . So, uh, so what |
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| 17:05 | see is that these impulses in time also serve, mate. But because |
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| 17:12 | separated in time, the longer the between these action potentials in a single |
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| 17:19 | on the longer the time, the time this E p s P has |
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| 17:24 | start re polarizing back. So the the frequency coming from a single |
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| 17:31 | the better is going to be in up this deep polarization to effectively reach |
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| 17:37 | action potential threshold. So again, types of summation spatial summation you're |
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| 17:45 | Several of the synapses are active at same time, activating this Boston optic |
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| 17:51 | , some mating and getting a much response just than than from a single |
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| 17:57 | and temporal summation. You have many potentials. Ah, frequency a certain |
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| 18:04 | of action potentials. There's a certain produced by the same Axiron, also |
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| 18:09 | to what we call temporal summation. , uh, when on the right |
|
| 18:17 | we're talking about is this diagram now our dendritic cable and the difference between |
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| 18:26 | dendritic cable and the so no cable a dendritic cable is not insulated. |
|
| 18:33 | we talked about action potential, sort producing acts on initial segment that then |
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| 18:39 | each note of Ron beer through the or conducting so that the amplitude of |
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| 18:43 | action potential is the same at the on initial segment as it is when |
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| 18:48 | reaches the external terminal. The mantra we know and that is because the |
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| 18:54 | are insulated. But den drives not insulated, and den drives are |
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| 19:01 | our leaky cables. So if you Jack current and 0.0 at this |
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| 19:09 | we call it the zero. this maximal current 100% of the current |
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| 19:16 | you're injecting if you have an electron very close to that side of injection |
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| 19:22 | , Jason, you will record quite large membrane potential change across the plasma |
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| 19:28 | here across the den drive. But second electro that would be located a |
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| 19:35 | distance away from the side of the current injection will only pick up a |
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| 19:42 | . Well, Onley pick up a off off this current, and you'll |
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| 19:50 | see a small change in V M a small, deep polarization. And |
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| 19:55 | because the current and this deep polarization current is gonna There's a resistance, |
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| 20:01 | there's going to be leakage across the cable. So den rides do prefer |
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| 20:10 | conduct towards Selma. That was the on the first section of the course |
|
| 20:15 | do prefer to conduct towards Selma. means that there is a certain anatomy |
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| 20:22 | the channel structure and expression that is that allows form or current to try |
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| 20:28 | reach the soma than the opposite direction the distal dendrite. When each one |
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| 20:35 | these dendritic cables and each one of cells may have a different, |
|
| 20:41 | length constant and length constant, here Lambda Okay, Lambda is the distance |
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| 20:52 | it takes for this current to decay 100% total value to decay exponentially into |
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| 21:02 | 37% off the Lambda values change, the lambda equals 37% or 370.37 off |
|
| 21:18 | V O, which is a total current here, and Lambda the Length |
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| 21:25 | than represents the distance and Michael Meters the signal will travel before it decays |
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| 21:36 | 37% of its total maximal value. the cables that are good for temporal |
|
| 21:47 | , especially, and spatial summation, are the ones that will have |
|
| 21:54 | long decay, right long decay that go thio here. Okay, this |
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| 22:01 | be a long length constant and in short lines constant. The current will |
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| 22:07 | down quickly. Mhm. So this this this DK more or less follows |
|
| 22:17 | this this constant rule of 37% maximum the total current indigent really cable. |
|
| 22:25 | now you understand that it's not only the current doesn't get regenerated, it |
|
| 22:31 | decreases as it travels down to drink . Campbell. And that's the reason |
|
| 22:36 | you need to activate many synapses in , or you actually activate trains off |
|
| 22:43 | potentials, high frequencies of action potentials order to some eight. The |
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| 22:48 | because that signal will decay down and be able to reach the soma |
|
| 22:53 | have a significant impact for the Soma de polarize enough to produce an action |
|
| 23:01 | is also what we call shunting and . So if you have an |
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| 23:06 | excited tourists, synapse and the part that signal will decay a portion of |
|
| 23:13 | signal of this large e p s that was generated a medicinal, done |
|
| 23:18 | ah portion of that deep polarization will be recorded at the level of the |
|
| 23:23 | . But in the situation where you have remember, we said that a |
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| 23:29 | of the inhibitory synapses are actually located to the soma in these person Matic |
|
| 23:36 | . So now if you have excited Synapse, which is active but at |
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| 23:41 | same time you have an inhibitory it is active is doing two |
|
| 23:45 | It's actually not Onley, causing an of chloride, um, hyper polarizing |
|
| 23:51 | cell. But it's also opening up channels and dispatch of the membrane and |
|
| 23:57 | for the current to escape. Acting a shunt for the cards to escape |
|
| 24:03 | channels are open now may be permissible these cards. They're traveling in the |
|
| 24:10 | , and now, at the level persona, you will see nothing so |
|
| 24:16 | the signal is a travel. So someone shunting some of these cards and |
|
| 24:22 | by this inhibitory synapse, gabber, , synapse can a no any of |
|
| 24:27 | exciting Terry input that you saw the of the dendrite that was pretty |
|
| 24:33 | So again, you would need for signal to some aides to overcome the |
|
| 24:38 | inputs and to overcome the Shan Finally, modulation is another way in |
|
| 24:46 | you can have either directly through the affecting channels will discuss this again. |
|
| 24:53 | called the shortcut path or through the protein coupled receptor. Now these air |
|
| 25:00 | these air much longer time scales to you probably a couple of receptor secondary |
|
| 25:06 | , including kinesis have been in was for late. The channels can |
|
| 25:11 | channel. So in this case, talking about norepinephrine. A will review |
|
| 25:15 | actions of what we're talking about here it affects potassium channel. But this |
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| 25:20 | be some module a Tory effects at level of the cell module, a |
|
| 25:25 | effects that would not affect the Good ometer GIC of gabby allergic |
|
| 25:30 | but would also affect very much or the state of activity off the active |
|
| 25:39 | to me. So let me, , again to summarize and to put |
|
| 25:45 | within the context, we've discussed several important systems. So we continue discussing |
|
| 25:52 | systems amino Assad systems, glutamate, and gabba. And we'll look into |
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| 26:00 | the cycling of glutamate and recycling of and recall that glutamate production into gabba |
|
| 26:09 | through Gamma Muna. Uh, said , our box delays eso all of |
|
| 26:15 | inhibitory itself will be expressing all of inhibitor into neurons. Gap allergic into |
|
| 26:20 | will be expressing. God, please that Siddle Colleen system know what happens |
|
| 26:26 | the Sudoku and Colleen chat. You acetylcholine, and then a subtle Colin |
|
| 26:31 | is breaks down acetylcholine in the serotonin . Um, you don't need to |
|
| 26:39 | these enzymes, but it's important to some of the functions of serotonin that |
|
| 26:46 | discussed with catacomb Olympians. Recall that scene l dopa, dopamine, norepinephrine |
|
| 26:52 | epinephrine. These are all very Got a colon means signaling molecules. |
|
| 26:58 | we've discussed you don't need to know enzymes involved here, but again, |
|
| 27:04 | should know, for example, that is important, and, uh, |
|
| 27:11 | Parkinson's disease, the epinephrine and norepinephrine like adrenaline of the brain, and |
|
| 27:19 | is also involved in a lot of function. L dopa is a |
|
| 27:24 | but L dopa and opening dysfunction is associated with schizophrenia. And in the |
|
| 27:30 | Cecilio Cobian system impairment, disassociated with disease that we discussed that's Alzheimer's |
|
| 27:37 | So again review the school in Arctic . That will be quite a few |
|
| 27:43 | an exam, questions on the seal signaling and the C. N s |
|
| 27:48 | comparing, um, actions between Moscow and the continent receptors, receptor subtypes |
|
| 28:00 | endogenous and exogenous agonists and antagonists. , uh, this is the shortcut |
|
| 28:09 | that we're discussing. So the shortcut is the pathway that is different from |
|
| 28:13 | one that I showed you through. regulation of the enzyme and secondary messenger |
|
| 28:19 | is shown here is this must carry receptor When a seed locally and biased |
|
| 28:24 | the academic reception, academic receptor is allow the flux of sodium and potassium |
|
| 28:31 | neck receptor. When acetylcholine binds, muscular neck receptor will acted a g |
|
| 28:35 | coupled receptor, and in the shortcut , it will not have any chemical |
|
| 28:41 | , but binding of acetylcholine will then that you put in sub unit and |
|
| 28:47 | sub unit will open up a potassium . So what's the difference? The |
|
| 28:53 | is potassium will be leaving the the influx of potassium. The cell |
|
| 28:59 | be hyper polarizing. If you activate academic receptor, the cell will be |
|
| 29:04 | polarizing. If you activate Mouskouri nick because it acts the potassium channel, |
|
| 29:10 | cell will be hyper polarizing. So can see that the same molecule can |
|
| 29:17 | different effects on the same cell. that same cell might be expressing two |
|
| 29:24 | , both subtypes of must Koranic and continent, acetylcholine receptors, gluconate. |
|
| 29:32 | important again that we come back and glutamate cycling again here because it z |
|
| 29:43 | two types of receptors for glutamate and review these receptors. And one of |
|
| 29:48 | is, uh, um, on a tropic receptor channels for |
|
| 29:55 | And then you have never been topic receptors. Boston optically to Once glutamine |
|
| 30:01 | released, it gets transported back into pre synaptic terminals and gets reloaded back |
|
| 30:10 | this citified protons, radiant back into vesicles for subsequent release. But a |
|
| 30:17 | of times as we know real cells but an incredible role. And cycling |
|
| 30:26 | these excited during their transmitters and cycling the ions. We talked about the |
|
| 30:33 | diffusion by glial cells by ostracized. in this case, glutamate will be |
|
| 30:39 | up by glial cells. Glutamine synthesis produce glutamine. That glue domain will |
|
| 30:47 | taken up into prison optic neurons through Tamponnaise is going to get produced and |
|
| 30:52 | up a glutamate into the vesicles. , so you can see that there |
|
| 30:58 | essentially neuronal glutamate, pathway off re of glutamate and Rio reloading of the |
|
| 31:06 | , or this longer degrading and re pathway for glutamate that brings it into |
|
| 31:13 | pre synaptic neurons. Now these neurons in will remain and they have |
|
| 31:21 | Then they will be able thio synthesized . And instead of looting mate, |
|
| 31:26 | will actually be gabbar entrepreneurs. So cola means again. We discussed the |
|
| 31:35 | of Cata Cola means, um and reciting this here and how again we |
|
| 31:44 | the drugs of abuse and also pharmaceutical affect can a column ian system very |
|
| 31:51 | for movement, mood attention and visceral . Serotonin system very important from |
|
| 31:57 | appetite, sleep and learning. Prozac a common antidepressant. Will ball re |
|
| 32:05 | of serotonin prolonging the Bible ability of serotonin, the synoptic clough. |
|
| 32:13 | if we look at the G pro and if we look at these |
|
| 32:20 | sometimes you can have two medical tropic acting in the opposite fashion, which |
|
| 32:27 | call the push pull mechanism so you have a neurotransmitter that binds and then |
|
| 32:35 | enzyme and activates downstream intermediary pathways. that neurotransmitter, this is an example |
|
| 32:42 | norepinephrine. You have norepinephrine, beta norepinephrine, Alfa two receptor. There's |
|
| 32:49 | different subtypes of norepinephrine receptors that are by either the same or different cell |
|
| 32:57 | . If norepinephrine binds the beta it's G protean Cascade will stimulate. |
|
| 33:05 | positive sign means it will stimulate a cycles production of cycling KNP and will |
|
| 33:13 | the levels of protein kindness, a Chinese say and kindnesses will force for |
|
| 33:19 | channels. So in this pathway, stimulating at a little cyclist. Increasing |
|
| 33:25 | of cycle can be an increase in of protein Chinese A. But if |
|
| 33:32 | binds nearby Alfa two receptor or Alfa receptor in a different neuron activation of |
|
| 33:39 | protein complex will result in the inhibition a general cyclist function and inhibition of |
|
| 33:46 | production of cycling, campy in an off the production of protein kindnesses |
|
| 33:54 | So kindnesses and foster Stasis kindnesses will for a late will. Add a |
|
| 34:00 | 04 group onto proteins and prospectuses will that group away. The protein kindness |
|
| 34:07 | hospitals levels of very important also in channels was for relating receptor channels and |
|
| 34:18 | so in general, the activity of molecules is dependent on the receptors and |
|
| 34:25 | location of the post synaptic receptors. would those receptors are whether they're on |
|
| 34:30 | tropic of medical trophic? This is in which we, in the case |
|
| 34:36 | Siddle Colleen we discussed opposing action off continent receptor, which is excited her |
|
| 34:42 | the CNS neurons vs musk sarinic which is inhibitory in the CNS |
|
| 34:49 | So this is I on a Tropic memorable Tropic. This is memorable. |
|
| 34:53 | versus measurable Tropic, meaning It's two tropic systems through the same neural |
|
| 34:59 | But different subtypes of the same receptor acting in the opposing fashion to each |
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| 35:05 | . This pull push fashion in general very important to know that these molecules |
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| 35:13 | , serotonin and and all the other that we already mentioned are expressed and |
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| 35:21 | nuclei in the central nervous system. norepinephrine in will be expressed by local |
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| 35:30 | IUs. Okay, norepinephrine will be by locus civilians and locus surreal |
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| 35:37 | A nucleus nucleus is a collection of or south. They're responsible for the |
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| 35:43 | or similar function of their located in same area or adjacent areas of the |
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| 35:49 | . And so Locusts Aurelius will produce , another nucleus. Ratha nuclei shown |
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| 35:58 | will be responsible for the production of and these arrows. These blue arrows |
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| 36:05 | the projections off these Nora Penner norepinephrine . These sprinkler, like synapse ending |
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| 36:16 | , usually project through the neocortex through cerebral cortex through thalamus and the hippocampus |
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| 36:23 | , other parts of the brain, the cerebellum, as well as projecting |
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| 36:29 | to the spinal cord. So norepinephrine here in the CNN s will then |
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| 36:35 | sprinkled throughout different structures in the and the response of the surface will |
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| 36:41 | on what some type of the receptors neurons with these circuits are expressing in |
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| 36:47 | case of norepinephrine A. They dominated half a to or by norepinephrine data |
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| 36:53 | , and therefore it's gonna be the in that particular region of that particular |
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| 36:58 | . Neuronal circuits. You can see against their don't in the search different |
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| 37:05 | from, uh, from norepinephrine Serotonin are also quite diffuse throughout the cortex |
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| 37:16 | cerebellum and from Raffi nuclei that are through the brain stem. Regions here |
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| 37:22 | also projected to the spinal cord. it's slightly different projection pattern of |
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| 37:28 | What we call non specific projections. we refer Thio Sprinkler system because it |
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| 37:33 | Sprinkle down serotonin or Sprinkle down Ephron non specifically def, usually throughout |
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| 37:41 | brain and then cause specific response, on the specific sometimes of the receptors |
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| 37:49 | and given south on your own will . So again, this is |
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| 37:53 | for example, that acetyl Colleen will produced by Magnus Cellular basal forebrain. |
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| 37:59 | for brain neurons, okay, we'll producing a lot of Seattle Colleen, |
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| 38:06 | so these neurons and these Colin ergic will be damaged early in Alzheimer's |
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| 38:13 | There's another place, but the donkey and lateral also took mamta nuclear here |
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| 38:19 | green that also produced the Seattle This is a raffi nuclei that produces |
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| 38:38 | . This is Locusts, Aurelius, produces norepinephrine. This is histamine production |
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| 38:45 | tuber man Ilary nucleus. This is . Take mental area of substantial Niagara |
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| 38:51 | produces dopamine. So that would be production of dopamine potential in these areas |
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| 39:00 | are associated with Parkinson's disease and uh, dental tech, mental area |
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| 39:07 | basil ganglia area, which are responsible , ah, lot of the motor |
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| 39:13 | initiation and find motor command. so we were painting. Here is |
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| 39:21 | picture that these neurotransmitter serotonin, norepinephrine these others, such as the Segal |
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| 39:29 | in the CNS, expressed in very nuclei in the brain stem or in |
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| 39:35 | certain parts of the cerebral, serene . And then they are def usually |
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| 39:41 | throughout different parts of the brain and spinal cord, as opposed to the |
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| 39:48 | opposed thio These molecules, which are in all of the south and the |
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| 39:59 | N s so excited, Terry, mean, ass is there not produced |
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| 40:05 | the specific nuclear. You can see that this produced and synthesized within the |
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| 40:13 | essentially within the neurons everywhere where you excited Terry synapses, you'll have synthesis |
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| 40:20 | glutamate. It's not that it gets from grain stem sources, so it's |
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| 40:25 | . Okay, this system sprinkler a specific thio mean their transmitter. |
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| 40:32 | we're talking about and it's different from Canavan Line neurotransmitters, too. Because |
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| 40:38 | the cannabinoids, they're also synthesized in different cells. Virtually almost every cell |
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| 40:44 | the body will have components of them cannabinoid system, which is under cannabinoids |
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| 40:49 | as Ananda Miter to our Arc Adonal and the CA nominal and receptor C |
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| 40:54 | one, and also CB two which we'll discuss later. And tetrahydrocannabinol |
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| 41:00 | a fiddle cannabinoid that's found in cannabis and, uh, th CIA tetra |
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| 41:08 | economic Nall. We'll also bind to one receptors. So these endogenous agonists |
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| 41:15 | CB one receptor under cannabinoids and this an exogenous THC is an exogenous |
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| 41:21 | Two CB one receptor both in the avenues and THC through activation of CB |
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| 41:27 | receptor will then regulate the release of excited during the inhibitory neurotransmitters of the |
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| 41:34 | . There's this retrograde signaling through this we call negative feedback system and |
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| 41:40 | This is different than being expressed in nucleus and released throughout. But in |
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| 41:45 | and in this case it's the cells almost every cell in the CNS will |
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| 41:51 | producing under cannabinoids. I mean, , neurotransmitters, it's getting a little |
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| 41:59 | repetitive, but we're redoing this and reminding you that both glutamate and GABA |
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| 42:06 | have sodium code transporters. So this be the neuronal code transport of glutamate |
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| 42:12 | addition to what we discussed and glial of glutamate. And then both Gabin |
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| 42:19 | will have their transporters onto the vesicles be transported in exchange for this proton |
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| 42:28 | number. The inside core of the are acidified. And so this protons |
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| 42:35 | , will drive both gather through Gabba into the vesicles of glutamate glutamate |
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| 42:43 | Now we're discussing blue dramaturgical neuro So this is how glutamate cycling priest |
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| 42:51 | optically and we looked at it and and glia. But what happens when |
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| 42:56 | gets released? We produce an P S P glutamate will actually target |
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| 43:02 | types off I on a Tropic Channel Tampa and M D. A and |
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| 43:07 | eight glutamate is ah endogenous agonist For glutamate receptors, these three I on |
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| 43:16 | tropic as well as medical tropic glutamate . But these receptors Ampara, an |
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| 43:24 | D Air Kaine aid have their uh features. And in addition, |
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| 43:31 | will only binds to ample glutamate receptor serve as an agonist and m d |
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| 43:36 | only to an M d A. not to Ampara conservatives. NMDA receptor |
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| 43:41 | . And so they're named after their agonists and distinguished, partly based on |
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| 43:47 | neuro pharmacology and kind name, will as an agonist to kind eight glutamate |
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| 43:55 | . Oh, so the pharmacology is fact that when you release glutamate, |
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| 44:05 | emperor receptors shown here in blue are to be active right away, they |
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| 44:12 | open an ample receptors will allow the of sodium causing, this initial deep |
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| 44:19 | and the re polarization. Nbsp happens there will be e flux of potassium |
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| 44:24 | the cells and then the heiress after adjacent are quite different. And in |
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| 44:30 | air receptors, it's not enough that is present in the synaptic cleft when |
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| 44:37 | , bond, stone M D receptors M d receptors unlike emperor receptors. |
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| 44:41 | then the receptors do not open immediately then the receptors have this magnesium blockade |
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| 44:49 | this magnesium molecule is literally physically blocking channel. And in order for this |
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| 44:56 | to leave the channel poor, the membrane VM has to change has to |
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| 45:03 | . All arise from minus 65 and it deep polarizes, he has shown |
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| 45:09 | minus 30 million volts. There will longer be magnesium. Magnesium will essentially |
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| 45:14 | kicked out of this channel poor and an M d. A. Channel |
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| 45:20 | going to conduct sodium and calcium and potassium out. Influx of more sodium |
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| 45:29 | cause further deep polarization. Influx of will cause secondary messenger cascades and |
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| 45:36 | Parson attic activation of channels on e of potassium will also contribute to re |
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| 45:43 | of the e p S d. this e p s P is difficult |
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| 45:48 | compound e p s P, meaning it represents activity through early part of |
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| 45:55 | PSB through the Ampara receptor channel. the late part of the PSB through |
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| 46:01 | m d a receptor channels the kinetics that Amper receptor is fast on the |
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| 46:09 | opens right away with glutamate binding and the a receptor requires deep polarization, |
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| 46:15 | it will take longer time to open if the receptor in order of one |
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| 46:20 | two milliseconds, depending on how hi a deep polarization. Selectivity, as |
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| 46:27 | can see in India, receptors will sodium, potassium and calcium, and |
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| 46:33 | ample receptors will allow select Onley for and potassium minds. Conduct INTs. |
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| 46:40 | Ince's. How much of the current how much of these ions can these |
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| 46:45 | conduct? And and then the A has larger conductors than Amper receptor |
|
| 46:52 | In the following slide, I actually that non NMDA receptors, and the |
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| 46:58 | why is because not NMDA receptors hampering interceptors do not have the magnesium |
|
| 47:06 | So there are a lot of Times that called non NMDA receptors. And |
|
| 47:11 | we'll conduct about 20 people Seamans, people Seaman's through the channel as opposed |
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| 47:19 | an M D A receptors, which going to conduct 50 PICO Seaman's So |
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| 47:25 | conductors through NMDA receptors as much larger ions mawr. Deep polarization will happen |
|
| 47:34 | you activate NMDA receptors, but at activate NMDA receptors. You have to |
|
| 47:41 | emperor receptors, and so everything that are talking so far about glutamate signaling |
|
| 47:49 | I on a tropic signaling this diagram in vicious medical tropic with inmates signaling |
|
| 47:55 | we will get to it. But confuse non in Indiana and DEA receptors |
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| 48:01 | I on a tropic versus memorable They're both all three subtypes and pocketed |
|
| 48:08 | m b a receptors are all I a tropic. That means that when |
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| 48:15 | ligand glutamate binds to the receptor receptor will open. When little mate |
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| 48:23 | to an m d heiress doctor, will also open. But coincidentally, |
|
| 48:32 | needs to happen is that there needs be deep polarization and there's also requirement |
|
| 48:40 | glide seen as a co factor, was like, Wait, wait, |
|
| 48:43 | , wait, wait. What are talking about? Lysine is inhibitory, |
|
| 48:47 | and, uh, spinal cord but glisten in the CNS, this |
|
| 48:56 | a different story. Gliding in the s will have a binding side on |
|
| 49:03 | glutamate and m d a receptors. if you have glycerine, the binding |
|
| 49:08 | glutamate will have a better impact on and agonizing this NMDA receptor. So |
|
| 49:16 | you have glutamate and glistened binding to and if the a receptor and you |
|
| 49:21 | deep polarization. Then magnesium, which a binding side here, is you |
|
| 49:28 | inside the poor. It probably has couple of binding sides along this |
|
| 49:34 | poor, but one of them is the pore blocking in. So this |
|
| 49:38 | what needs to happen. Positive charge to build up. In order for |
|
| 49:42 | magnesium thio, leave an M D channel, but this channel in MD |
|
| 49:50 | is an eye on a Tropic and once it's open and will conduct |
|
| 49:56 | inside potassium inside and s sodium and into the cell and potassium from inside |
|
| 50:05 | cell to the outside of himself so can see that NMDA receptor requires deep |
|
| 50:14 | , and it requires gliding go Deep polarization is required to remove the |
|
| 50:22 | block, and the go factor gliding required for the proper maximal activation of |
|
| 50:30 | receptors. Of course, there's other sites for sink. There's also binding |
|
| 50:39 | for PCP, which is an illegal drug and quite dangerous, addictive, |
|
| 50:48 | often acute schizophrenia with self mutilation on , severe hallucinations with psychosis. It |
|
| 50:56 | be permanent. Uh, because it a very, very profound. The |
|
| 51:02 | on an M d A receptors. there's also M K 801 which is |
|
| 51:10 | type off agonist. It's in, , it on Lee. It's an |
|
| 51:20 | agonist and antagonist, which means that binds the receptor when the receptor has |
|
| 51:25 | active so it doesn't block. The doesn't bind to this receptor until we |
|
| 51:30 | and Glide Scene has opened up this channel, so we'll discuss a little |
|
| 51:36 | about M. Kato one. We come back in the following |
|
| 51:43 | We're not running out of time, when we come back, we'll continue |
|
| 51:47 | about NMDA receptors. Welcome to review slides, and we'll talk about some |
|
| 51:54 | these curbs for an M D and . A receptors. How genetics can |
|
| 52:00 | the conductivity in this case, through receptor. One of the silence synopsis |
|
| 52:07 | very cool stuff. Then we will upon not only the eye on a |
|
| 52:14 | signaling, but also medical topic glue are signaling medical topic would have |
|
| 52:19 | receptor signaling and how it's different from on a tropic with the man who |
|
| 52:24 | signaling general talk about GABA, and actually talk about GABA, A Receptors |
|
| 52:31 | and the binding sites that are president GABA, a receptors that are very |
|
| 52:35 | , such as benzodiazepines, neuro steroids perpetuates and ethanol. Happy Hour. |
|
| 52:42 | , we'll discuss also the two signaling for Gabba Gabba Hey, which is |
|
| 52:48 | on a Tropic and Gabba B, is a matter of a trophic |
|
| 52:53 | You will learn that Galba V receptor control potassium channels and calcium channels versus |
|
| 53:01 | , a receptors permissible to chloride. so these air all of the topics |
|
| 53:07 | we still stand to discuss. We'll it, all of them. The |
|
| 53:11 | of Gabba and Gabba be signaling in neurons. It's getting pretty and pretty |
|
| 53:18 | day, and I'll show you some the experiments that I worked on myself |
|
| 53:23 | describing Galba and Galba be signaling in visual follow most. This is from |
|
| 53:29 | article in Journal Neurophysiology in 2000 and , and then finally, we'll review |
|
| 53:37 | structure after all of this function, signaling will review a little bit about |
|
| 53:41 | structure G podiums compare them to a gated channel structures and kind of |
|
| 53:51 | summarizing or pharmacology molecular analysis of follow receptors channels and finish by talking about |
|
| 53:59 | cascades and amplification through these messenger So there's still quite a bit of |
|
| 54:05 | left to cover for the synaptic But for the quiz, I would |
|
| 54:11 | recommend to review the last two lectures come prepared for the lecture on Thursday |
|
| 54:20 | we have Happy Hour on Thursday in form of the quiz starting at 12 |
|
| 54:28 | So don't forget, then it's coming . And don't forget that I will |
|
| 54:32 | ask you a question or two about two or three upcoming slides. And |
|
| 54:38 | you're welcome to review these slides and ahead of time, okay, and |
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| 54:43 | a |
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