| 00:00 | or This is neuroscience lecture four and me posit and dim the lights in |
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| 00:09 | classroom. What we discussed last lecture the diversity of the neuronal circuits in |
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| 00:19 | . We focused on hippocampus and we about many important things about hippocampus. |
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| 00:26 | we actually talked about the circuit, diversity of the inhibitory cells, how |
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| 00:31 | would be recognizing and what techniques you need to use in order to identify |
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| 00:38 | subtype of cell. We talked about fact that into neurons, although they |
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| 00:44 | 10-20% of the total self population in circuits like in Hippocampus or neocortex, |
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| 00:51 | only 10-20% of the total self population neurons that 80-90% are actually parameter all |
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| 00:58 | of projection cells but the variety of internal organs in the circus provide for |
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| 01:07 | and computational power and computational aspects of circuits and parameter cells are communicating. |
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| 01:15 | different rhythms and modulated activity by the neurons into the surrounding networks. We |
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| 01:23 | talked about what the function for hippocampus and we discussed semantic memory. So |
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| 01:30 | talk about plasticity and you'll see the and these pathways. This is a |
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| 01:36 | . One area of the hippocampus and pathways between C. Three and |
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| 01:41 | A. One and dental gyrus. part of the campus are very common |
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| 01:47 | of studying cellular plasticity in neuroscience and fact what we know about cellular plasticity |
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| 01:54 | learning and memory comes from studying this . So it's probably the most studied |
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| 02:00 | probably the most celebrated circuit apart from new york cortex in the brain is |
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| 02:05 | hippocampus and it does serve a very function and it is an archaic cortex |
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| 02:10 | predominantly three layer structure. So all this information, if you recall in |
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| 02:16 | article with precise descriptions of the figure in your class supporting materials. So |
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| 02:24 | can open that article and reread but will not be responsible for more than |
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| 02:30 | we discussed in class. But it's great tool in helping you and you'll |
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| 02:35 | that this variety of cells represents a of dialects and these dialects are really |
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| 02:43 | . The cells would produce the frequencies the sequences of the action potentials and |
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| 02:51 | variety again and the firing properties of cells comes from the inhibitory into neurons |
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| 02:58 | they're mostly into neurons because they control activity locally and they're excited. They're |
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| 03:04 | cells of projection cells because they communicate project out of the local circuits into |
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| 03:10 | other parts interconnected parts of the We also discussed neuro biden or by |
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| 03:16 | and so please know the difference between dye Golgi stain and this will stain |
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| 03:21 | any other dyes that we have may mentioned in the sports or or or |
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| 03:25 | mentioned. Uh It's a very important in the history chemistry and you |
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| 03:30 | histology is something, it's very simple again as a technique by which you |
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| 03:36 | electrical activity from single cells, networks the whole brain and reconstructions are cell |
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| 03:45 | is obviously being able to reconstruct and all of the processes the dendrites and |
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| 03:50 | axon is off the cells that you're with reporting from targeting otherwise and so |
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| 03:58 | . There's basic organelles where I'm going skip over it already reviewed it. |
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| 04:05 | going to remind you that we talked autism spectrum disorder and in particular we |
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| 04:09 | about fragile X syndrome. So remind why it falls under autism spectrum disorders |
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| 04:18 | there is an important pro dan FM that gets expressed and it's a genetic |
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| 04:25 | fragile X. And so if you're the gene that makes the protein FM |
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| 04:32 | , the more of that gene you're and the less of that protein you |
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| 04:36 | , the more severe symptomology is going be in fragile X syndrome, one |
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| 04:41 | the pathologies that you would see on cellular level and even on sub cellular |
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| 04:46 | is abnormal dendritic spine formation and abnormal spine densities. So the morphology of |
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| 04:54 | spines, it's very different in these retardation cases. There's also some outward |
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| 05:02 | of fragile X. That Children may elongated years and very large foreheads in |
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| 05:07 | , very long shaped faces. But that does not necessarily equate to a |
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| 05:16 | dysfunction. It's the other way around neurological dysfunction, fragile X will resolve |
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| 05:20 | some uh elongation of some of the features so excited during, inhibitor of |
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| 05:29 | is the this is where most of contacts is made on the dendrites and |
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| 05:34 | expands and soma. Soma. Soma to integrate the glutamate, ergic and |
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| 05:39 | ergic synaptic activity and decide whether it's to produce an action potential and when |
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| 05:46 | produces an action potential is going to neurotransmitter chemical at the external terminal and |
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| 05:52 | synopsis that is communicating to another And we stopped here last lecture and |
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| 06:00 | I started explaining to you that um diagram is very important and we're not |
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| 06:07 | uh spend like a whole hour on but we'll spend 10 15 minutes talking |
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| 06:14 | it. There might be a few on this of the exam too, |
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| 06:18 | this is really the dynamics behind the potential and the graduate level, my |
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| 06:25 | courses really confusion with an undergraduate So this qualifies as a graduate course |
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| 06:33 | this graduates to level you really need know these concepts action potential. Free |
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| 06:39 | frequency amplitudes of action potentials and so . So what is illustrated here, |
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| 06:45 | of all is the resting membrane potential resting membrane potential is abbreviated as |
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| 06:50 | And P. And the value for membrane potential is approximately negative 65 |
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| 06:56 | And does that mean that at rest measuring this electrical activity from the |
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| 07:05 | You're recording this activity and and you're on that Read out of this |
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| 07:12 | This is zero minus 65 kilovolt readout the volt meter From the south from |
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| 07:20 | Electrode. Does that mean that this -65 is going to be a flat |
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| 07:26 | . And I always explain that nothing biology is a flat line actually. |
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| 07:30 | have a flat line can be in much one thing. Uh Yeah. |
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| 07:37 | you hear that he that's a flat . So what happens to the resting |
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| 07:42 | of potential is it really only at 65 million balls. Now it actually |
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| 07:47 | and it goes down and it goes and it goes down and it goes |
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| 07:52 | . And the reason why it goes is because it receives glutamate inputs that |
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| 07:57 | excitatory and they de polarize the And the reason why it goes down |
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| 08:03 | because it receives gaba inputs and those inhibitory and they will hyper polarize the |
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| 08:11 | drive into more negative potentials. So constantly have the fluctuations and neurons general |
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| 08:19 | not very active and they're not firing potentials. So those frequencies that you |
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| 08:23 | is when you inject a lot of from the stimulus are strong, they |
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| 08:27 | respond with that sequence and frequency of potentials. In general, if the |
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| 08:35 | you're doing an experiment and you were an experiment and sink an electrode into |
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| 08:39 | neuron that's not necessarily receiving direct and stimulus. It may just fluctuate and |
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| 08:48 | one action potential once in a while go back to resting membrane potential. |
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| 08:53 | this this up and down a lot times is referred to as a random |
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| 08:58 | if it receives more excited, there synopsis To reach if it receives enough |
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| 09:06 | synopsis to reach this -45 million volt . This is the action potential threshold |
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| 09:13 | -45 at which point that this yellow , it will produce an action |
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| 09:19 | So the cell dynamics are such that will fluctuate up and down. But |
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| 09:24 | it reaches this threshold that will produce or not. And once it starts |
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| 09:29 | an action potential, it will always the same or very similar amplitude, |
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| 09:34 | same or very similar shape. The beyond the action potential is the rising |
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| 09:40 | . You will have a lot of flexing into the south and on the |
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| 09:44 | phase you have potassium flexing out of cell. And there are these concepts |
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| 09:51 | that I drew the equilibrium potentials of equilibrium potential for sodium chloride. Uh |
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| 09:58 | , calcium, sodium chloride and Now the equilibrium potentials. Again, |
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| 10:04 | don't have those diagrams in your So, for those that are not |
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| 10:11 | familiar and for those that may need refresher because uh they may have forgotten |
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| 10:18 | most important things here. And understanding in physiology is to know that there |
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| 10:23 | an uneven distribution of ions across plasma that's sodium and chloride are dominating on |
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| 10:33 | outside of the plasma membrane and potassium dominating on the inside of the side |
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| 10:39 | plasma. And this 80 p. which used a teepee for energy, |
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| 10:47 | sodium and potassium against their concentration So the plasma membrane has all of |
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| 10:55 | proteins and a lot of them are channels that are embedded. These channels |
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| 11:00 | selective and specific to specific islands. sodium ion channel is going to allow |
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| 11:07 | ions to go through but not potassium is gonna allow potassium and sodium |
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| 11:11 | so on. Now. The these are not always over these channels that |
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| 11:19 | talking about. When you talk about dynamics of the action potentials, we |
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| 11:23 | them voltage gated channels. There are protein channels that can be gated by |
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| 11:29 | . That means that the change across membrane and voltage will open these |
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| 11:34 | There are channels that can be opened Liggins. That means the binding of |
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| 11:38 | chemical will cause the opening of the on the program. There are also |
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| 11:44 | that are mechanical obligated, meaning that a mechanical pressure, the displacement of |
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| 11:50 | displacement of pressure, mechanical pressure will the opening of that channel. But |
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| 11:55 | we talk about the action potential we're talking about voltage gated channels and |
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| 12:01 | voltage gated sodium and voltage gated potassium that account for the rise in the |
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| 12:07 | phase of the action potential. you have the concentrations of potassium on |
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| 12:13 | inside versus outside and these are the dominant ions when we talk about membrane |
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| 12:20 | resting membrane potential and also action You can also represent this mila molar |
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| 12:28 | in ratios how much 5 - 100 the same as 1 - 20. |
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| 12:35 | there's 20 times more potassium on the and on the outside. But I |
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| 12:42 | say please pay attention to calcium because has the highest disparity in the concentration |
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| 12:49 | across plasma membrane. And calcium in is not only just an ion developed |
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| 12:56 | , it's also a secondary messenger. in your arms in general and sells |
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| 13:01 | wouldn't have unless there's some special function their cells. You wouldn't have that |
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| 13:05 | of side a solid calcium floating Most of it gets bound up by |
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| 13:10 | binding protean calcium calculators and stuff. now having so much calcium on the |
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| 13:19 | means that there's a huge concentration gradient the castle to come inside. What |
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| 13:26 | that mean that the membrane addresses most to calcium? The answer's no addressing |
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| 13:33 | in potential. The cell is leaky the cell is most permissible to |
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| 13:40 | So as the resting number in potential going through these fluctuations, the most |
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| 13:45 | ion that's flexing through these channels is uh leading the cell for for hyper |
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| 13:55 | zones and sodium coming in and potassium . But mostly the cell is permissible |
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| 14:00 | potassium. This constant load of potassium high concentration and potassium is slowly leaking |
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| 14:07 | of the cell. This is just way neurons behave. Okay. And |
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| 14:11 | lot of times you will hear in read about the leak channels like a |
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| 14:17 | or leak currents and these are potential leak channels and potassium leak currents. |
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| 14:24 | addition to this concentration gradient, you have a qua Librium potential for each |
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| 14:29 | . And I have that equilibrium potential your power point presentation. But you |
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| 14:36 | see that there's different numbers for equilibrium , equilibrium potential is a potential at |
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| 14:46 | if you have a high concentration gradient one eye on on one side of |
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| 14:50 | membrane and low concentration gradient on the side of the membrane and then the |
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| 14:55 | concentration gradient if the channel is open say sodium ion will start rushing across |
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| 15:01 | membrane and then if everything was okay you would have equal concentration on both |
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| 15:08 | on both sides. But remember that are charged And so when ions cross |
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| 15:14 | membrane positive ions, they also become to their own positive charge. And |
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| 15:20 | moment at which the concentration gradient is , the best way to describe it |
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| 15:29 | this if you have a lot of is potassium when the channel is open |
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| 15:34 | flow across plasma membrane but it will reach an equal model of concentration because |
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| 15:42 | build up of the positive potassium charge this side of the membrane will actually |
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| 15:47 | repelling the positively charged potassium at that the concentration gradient on the left, |
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| 15:53 | lot of that chemical, it's still potassium across the membrane but the electrical |
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| 16:01 | is driving that potassium in the opposite . The two forces become equal and |
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| 16:07 | in each other and when they become that equal and opposite uh state that |
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| 16:15 | is the equilibrium potential and that value the equilibrium potential value. Okay, |
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| 16:25 | this is for potassium and of course have the same for sodium, sodium |
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| 16:32 | start rushing inside the cell but then will have a build up off the |
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| 16:38 | that will start repelling sodium as Uh huh. And so to calculate |
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| 16:46 | equilibrium potential we use nonstick equation and is a nuanced equation and the nonce |
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| 16:55 | is 2.303 or E ion equals R. T Z. F log |
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| 17:04 | ionic concentration on the outside versus the concentration on the inside of the |
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| 17:11 | R is the gas constant, ease temperatures, ease the valence. So |
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| 17:16 | one is mono valiant two pluses die F. Is electrical Faraday constant log |
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| 17:24 | on logarithms ions on the outside ions the inside. And so each one |
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| 17:31 | these ionic species, potassium sodium chloride calcium have their own equilibrium potential. |
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| 17:39 | you can collapse 2303 rtz F. 61 50 for Because you're recording it |
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| 17:46 | a physiological temperature 37°C. Or you're calculating the physiological temperature And you can calculate |
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| 17:55 | abbreviation and then plug in potassium values sodium values chloride and you can see |
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| 18:03 | this abbreviation becomes 30.77 for calcium because is a development ion so it would |
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| 18:09 | divided by two over here. So half of 61.50 for 30.77. And |
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| 18:17 | you run through this calculation for each , you will find out that each |
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| 18:21 | of these ions have their own equilibrium values -8060 - 1 23, 16 |
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| 18:30 | . But equilibrium potential will allow you calculate the reversal potential of equilibrium potential |
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| 18:38 | for one ion. And overall numbering is not dictated by one ionic |
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| 18:45 | but rather the interaction of sodium and and in part chloride. So there's |
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| 18:51 | formula that is used to calculate the potential and that's the Goldman equation. |
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| 18:57 | differences between neurons and Goldman equation are in Goldman equation you have more than |
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| 19:03 | ionic species. You are now using same abbreviation R. T. |
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| 19:08 | F, which is 61 50 formula logarithms. But instead of just one |
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| 19:15 | for potassium, you're using potassium and . And the other thing is you're |
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| 19:21 | permeability. So if the channel or the cell is more permeable to that |
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| 19:29 | , then it will favor essentially that ion and it will be drawn toward |
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| 19:36 | reversal potential equilibrium potential for that particular . And so if you plug in |
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| 19:42 | values potassium on the outside versus potassium the inside, sodium on the outside |
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| 19:49 | sodium on the inside are TCF abbreviation And take a log of it. |
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| 19:55 | actually derived what we call the resting of potential value of negative 65 million |
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| 20:01 | . So the difference is between non . There's a single ion equilibrium potential |
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| 20:07 | called it reversal potential. Goldman equation a resting membrane potential which incorporates the |
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| 20:15 | and potassium and you can add in if you want and see if it |
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| 20:19 | the resting membrane potential much. So can do that on your own experiment |
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| 20:25 | you want. You don't have So these are the major differences between |
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| 20:31 | two equations and I will make sure I will post up those three slides |
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| 20:36 | there election materials. Ah And so on this chart, I have inserted |
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| 20:44 | equilibrium potential values. So these are reversal or norms potential values for calcium |
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| 20:51 | sodium chloride and potassium. And it's because I want to explain to you |
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| 20:59 | action potential as it relates to the potential values and not just in flux |
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| 21:07 | reflux. So I said that a number and potential here before it reaches |
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| 21:14 | threshold, the cell number and his formidable to potassium. And so you |
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| 21:19 | see that The resting membrane potential of even if you did that calculation for |
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| 21:25 | and potassium is very much favorite potassium there's huge permeability for potassium. |
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| 21:31 | it's a huge permeability for potassium and right, that's not what I |
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| 21:43 | Uh there's a huge permeability for potassium . But when the cell reaches the |
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| 21:49 | for action potential now you turn on you open sodium channels and you have |
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| 21:57 | influx of sodium and the more deep you have, the more influx of |
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| 22:02 | you have. And what sodium is is sodium is driving the overall number |
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| 22:07 | potential. Remember that this blue traces overall number of potential that you're |
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| 22:12 | which is a collection that represents all these ionic species crossing through the |
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| 22:18 | So now you're basically going through this feedback cycle and sodium island is trying |
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| 22:24 | drive the overall numbering potential into the potential value for sodium but it fails |
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| 22:31 | do so because there are certain sodium dynamics that shut down sodium channel so |
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| 22:37 | activates fairly fast. And at that you can see the potassium now, |
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| 22:43 | very far away from its own equilibrium . So with the potassium is trying |
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| 22:48 | do is going to try to the enough to reach the equilibrium potential value |
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| 22:55 | learns potential value for potassium and then NHK prompt will slowly rebuild this |
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| 23:04 | The other thing is during the action during this phase we call absolute refractory |
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| 23:09 | phase of the action potential, you produce another action potential. So, |
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| 23:13 | you try to force the cell, gave another very strong stimulus during the |
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| 23:18 | potential. The number and wouldn't produce action potential on top of this |
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| 23:24 | And higher amplitude, it has to polarize. It has to re polarize |
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| 23:30 | has to come back to at least level below the threshold for action potential |
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| 23:36 | , at which point it enters the refractory period. At that point the |
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| 23:43 | that received in this immediate point, it received a very strong fast |
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| 23:49 | it would immediately produce another action And so again, the strength and |
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| 23:55 | frequency of the frequency of the action A lot of times represents the strength |
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| 24:01 | the stimulus. Now, action potentials generated at the axon initial segment and |
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| 24:11 | is the axon right here in green these are the damn rights and an |
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| 24:16 | initial segments as well as in those round beer. And these are the |
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| 24:22 | and Myelin nation. So Axons and ated uh in the central nervous |
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| 24:35 | But we ourselves called illegal Deandra sites these illegal dangerous sites. They have |
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| 24:49 | processes. And one of these processes a and installation a Myelin insulation around |
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| 25:04 | axon. And so you'll have the a legal Denver sides making these no |
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| 25:13 | the installation here around the axons with processes. And this break here is |
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| 25:21 | to as note of Ron dear. so when And the cell, let's |
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| 25:30 | , generates an action potential in the initial segment here will produce an action |
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| 25:38 | , that action potential will regenerate and note around here And that's because just |
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| 25:46 | an axon initial segment or acts on hill up nodes of ranveer contained very |
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| 25:51 | densities of voltage gated sodium and voltage potassium channels. And the reason for |
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| 25:58 | regeneration of action potential at each break note. Of round beer is so |
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| 26:04 | the amplitude of the action potential that produced at the axon initial segment is |
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| 26:12 | regenerated and when it reaches the external to release neurotransmitter here, the amplitude |
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| 26:20 | the action potential is the same as it started here initially effects on the |
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| 26:25 | segment. Okay. Yeah. So is an example of note over and |
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| 26:37 | and acts on the nerve sodium channels in green and potassium channels in |
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| 26:48 | And there's some protein KASPER Sir junction that's labeled too. So 1 1 |
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| 26:57 | action potential. So when you have voltage and mila vaults where you're measuring |
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| 27:10 | . Okay, This is your This is your -45 de polarize the |
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| 27:19 | . You produce an action potential to polarize the cell. It's an action |
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| 27:26 | . Don't do anything. So when produce this action potential it gets produced |
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| 27:33 | at the axon initial segments all the will come into the south and if |
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| 27:38 | positive input wins the positive input wins accident initial segments will produce a spike |
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| 27:49 | spike will get regenerated at each note around here and when it reaches the |
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| 27:54 | oil terminal. Yeah it will also me generation. So when it reaches |
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| 28:02 | external terminal and external terminal you have vesicles and these vesicles are filled with |
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| 28:11 | . And so what this axon action does when it reaches external terminal it |
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| 28:17 | a lot of positive charge and that charge opens calcium channels. So a |
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| 28:26 | of times you will see the language C. A. Two plus |
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| 28:33 | That means it's calcium two plus and V. Stands for voltage gated channel |
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| 28:40 | then you can have C. V. One maybe see a |
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| 28:46 | Two different types subtypes of these voltage calcium channels. So when when this |
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| 28:52 | polarization comes in here, calcium enters the cells and because of entrance of |
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| 29:00 | inside the cells now you have the fusion and release of the neurotransmitter in |
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| 29:08 | synaptic cleft. So two things without you cannot have neurotransmitter release. You |
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| 29:15 | to have deep polarization and you have have calcium entry. If you did |
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| 29:20 | experiment and you took the costume outside the outside of the south from the |
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| 29:26 | in which your bathing neuron you would see any neurotransmitter release. So you |
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| 29:32 | still stimulate the action potential you can stimulate the cells produce action potentials. |
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| 29:38 | if you had no calcium or if block voltage gated calcium channel. So |
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| 29:44 | are blockers who learn about antagonists and running about them today for glutamate |
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| 29:51 | If you block the calcium channel, do not get the release of the |
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| 29:57 | is a special interaction that happens between and the the secular protein complex. |
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| 30:06 | this is the vesicles, this is the testicle looks like and it has |
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| 30:10 | different proteins surrounded. Ah And on protein complex there is calcium sensing site |
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| 30:20 | to as synaptic fragment as a specific site that detects calcium influx. And |
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| 30:27 | these proteins on the vesicles all they V snare protein complex. Once these |
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| 30:34 | complexes on the vesicles detect calcium now actually merge and bind together with the |
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| 30:46 | membranes near complexes or the complex of that exists on the cytoplasmic of the |
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| 30:53 | of the membrane. And the protein complex interaction is what draws remember this |
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| 31:02 | to the plasma membrane and causes the of the phosphor lipid bi layer of |
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| 31:08 | vesicles with the phosphor lipid bi layer the axon membrane and exocet. Oh |
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| 31:15 | of neurotransmitter into the synaptic cleft. that the vesicles are actually surrounded by |
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| 31:24 | molecules and they are pinched off and back in or endorse it toes back |
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| 31:31 | . So vesicles never leave that piece the membrane is preserved and stays with |
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| 31:38 | with neurons. So this is the cycle of producing an action potential If |
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| 31:45 | reach the threshold. If you reach threshold it's all or non event. |
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| 31:50 | you have that event it will regenerate with each note of wrong dear. |
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| 31:56 | will cause influx of calcium through this polarization, bicycle fusion and neurotransmitter |
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| 32:06 | And after the exercise ketosis you also endo psychosis. So the major neurotransmitters |
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| 32:13 | the brain. We're discussing the excitatory glutamate and they inhibit the american splinter |
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| 32:27 | . They're both amino acid neurotransmitters, third major amino acid neurotransmitter in the |
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| 32:37 | that lives in the spinal cord it's . So when we talk about excitatory |
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| 32:44 | cells those are the cells that make synthesized glutamate and release glutamate. When |
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| 32:52 | talk about inhibitory inter neurons or local neurons we talk about the cells that |
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| 33:01 | and release gaba. And of course in this the cells that synthesize and |
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| 33:07 | splicing glitter. Makes. So in spinal cord, basically the major inhibitory |
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| 33:15 | is glycerine and in the cortex of tissues. Everything up from the spinal |
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| 33:21 | up brain stump is Gabba. But you will learn is a go factor |
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| 33:29 | glutamate signaling in the CMS when we about the M. D. A |
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| 33:34 | functions. So this is glutamate right and at the bottom is gaba. |
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| 33:43 | glutamate will contain this car box el age group and the inter neurons. |
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| 33:53 | that will carry gaba will convert glutamate platonic musical atomic acid d card box |
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| 34:01 | will declare Boxley glutamate and turn it gather. I really like this because |
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| 34:10 | are the functions of glutamate and Gaba so different Plus and minus and a |
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| 34:16 | rough scale. But the two molecules one Reaction, one enzyme away from |
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| 34:23 | another and you also don't have to so then the amount of Gaba has |
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| 34:30 | depend on overall amount of glutamate. is the pre courage to garbage. |
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| 34:41 | you ever thought what if you don't glutamate? Do you have anything to |
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| 34:48 | you do you do you have got if you don't have you don't have |
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| 34:51 | . So it's it's it's an all the inter neurons that will be releasing |
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| 34:56 | . They will all uh test positive the atomic assets. Speaker box |
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| 35:03 | So you could immuno histological e test for G. A. D. |
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| 35:09 | and they will have God and And that's another way in histology, |
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| 35:13 | histology in which you could identify the of inhibitory styles on the circuit. |
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| 35:20 | a good way to identify all inhibitory . But it's not a good way |
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| 35:24 | identify specific subtypes of inhibitor cells which have to go through several hoops experimentally |
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| 35:32 | to do that. Okay, so are the major amino acid neurotransmitter Bryant |
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| 35:44 | in general when you think about, and glitter made. I want you |
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| 35:48 | think about the balance in the There is a certain balance between glutamate |
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| 35:57 | Gabbana. There's a certain balance between or inhibitory synapses. Is that balance |
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| 36:04 | balance? I mean there's certain levels balance checked, modulated and controlled activity |
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| 36:12 | there there is some sort of a and we know that if you have |
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| 36:17 | you would call a chemical imbalance in brain, you can think of it |
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| 36:22 | these very rough terms. That can an imbalance and excitation or inhibition. |
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| 36:29 | that mean that this balance is again a flat client that always stays |
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| 36:35 | Or does it mean that it constantly fluctuating a little bit, willed it |
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| 36:42 | a little bit up and just moving a normal dynamic range of the brain |
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| 36:51 | normally within its dynamic range. Within balances. Right. What happens if |
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| 36:58 | all of a sudden tilt this forward and now the excitation, if you |
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| 37:12 | in the balance would be dominating and wouldn't have enough in addition. |
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| 37:18 | What about the opposite case? What there is too much inhibition and that |
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| 37:24 | the other than ways the scale toward ? Okay. Towards gamma. So |
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| 37:31 | of these scenarios are possible and these really the balance when we look at |
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| 37:36 | balance of the brain, it's not that simple is God glutamate and gaba |
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| 37:42 | we have a number of other very chemicals in the brain neurotransmitters and neuro |
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| 37:50 | . And this is a good summary them in the C. N. |
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| 37:54 | . You have acetylcholine which is synthesized acetylcholine and co a little choline and |
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| 38:04 | . Acetylcholine is an amine neurotransmitter. can you say means plus or |
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| 38:19 | It actually means both. So the itself, the result of the response |
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| 38:26 | the cell depends on what receptor that binds. Uh serotonin is a very |
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| 38:37 | molecule. Mhm. The precursors trip fan and you have five hydroxy trip |
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| 38:44 | fan and then you have five HtP serotonin cata cola means are also very |
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| 38:52 | when you have a number of cata means such as tyrosine dopa dopamine, |
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| 38:57 | and epinephrine. What is the point the slide for For those that I |
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| 39:04 | be seeing it the first time. point of the slide is that you |
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| 39:08 | find gaba ergic and uh uh blue neurons throughout the cortex of cortical |
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| 39:18 | But the neurons that produce art all neurons that produce norepinephrine dopamine up enough |
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| 39:24 | they live in very specific nuclei in brain stone. And they just have |
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| 39:29 | that project into the cortex that they find the smaller parts of the |
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| 39:34 | So if you looked at the brain and said okay I want to know |
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| 39:40 | example this is this is the brain down. Okay I want to know |
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| 39:49 | glutamate salsa located and you did a for glutamate neurons and you will find |
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| 39:56 | everywhere everywhere everywhere everywhere everywhere everywhere. you say, I want to know |
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| 40:01 | gamma saucer located uh and you will Jabba cells everywhere, everywhere, |
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| 40:08 | everywhere everywhere. And then you will , well I want to know where |
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| 40:14 | the cells located that produce serotonin And you use them, you know histology |
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| 40:22 | stan you'll find, oh they're the is of the salsa producer Fellman. |
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| 40:29 | there are the projections that are going centrally and peripherally off the serotonin. |
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| 40:39 | the so most of the serotonin producing will only be here and nowhere |
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| 40:46 | Okay, so amino acids, amino is everywhere in the brain. The |
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| 40:54 | that synthesize in small organs. It other neurotransmitters that we're talking about but |
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| 41:02 | all means they are producing specific Does that mean that only here you |
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| 41:10 | find that chemical, know you'll find wherever the projections of that chemical go |
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| 41:18 | again, you can view these systems modular Torrey systems. Now you have |
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| 41:25 | scale, the balance of E. of your plus and minus. But |
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| 41:34 | not that simple. And what these would do is they would introduce all |
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| 41:42 | of different nonlinear variations over both the stays and time in controlling the plus |
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| 41:54 | the minus and the balance of the and the minus. So these are |
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| 42:01 | torrey substances glutamate. As I all of these cells for example, |
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| 42:08 | of the throttle cells that you'll see the brain. They're producing glutamate. |
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| 42:15 | all of these, let's say uh dot parameter cells everywhere here, everywhere |
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| 42:24 | see a dot anywhere that will be glutamate. And so in pre synaptic |
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| 42:32 | you'll have glutamate is packaged in the because the binding of the vesicles release |
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| 42:38 | glutamate will bind to post synaptic glutamate . And then that glutamate and in |
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| 42:46 | neurotransmitters that get released in the synaptic . They don't hang around there that |
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| 42:51 | . They get bound up by the protein. These are ligand gated |
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| 42:59 | They're not voltage gated channels. So talking about the chemical will now vie |
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| 43:03 | open the channel in the membrane potential action potential. It was voltage that |
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| 43:08 | opening sodium potassium channels. That we'll get recycled. There's glutamate transporters |
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| 43:15 | the neurons will get recycled back and in the neurotransmitter vesicles at the same |
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| 43:24 | , there is glial glutamate transporters. remember the tripartite synapse and the astrocytes |
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| 43:31 | astrocytes most important glia that play a in synaptic activity, plasticity and synaptic |
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| 43:38 | even during early development, they supervised of glutamine, the intake glutamine with |
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| 43:47 | synthesis will turn it into glutamine and contaminated is then that glutamine can be |
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| 43:54 | into neurons and with contaminates that the will convert it into glutamate and loaded |
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| 44:00 | into the vesicles. So the amount the excited to amino acids that are |
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| 44:07 | here locally and everywhere you have these here are now controlled locally by the |
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| 44:14 | and their processes that help them regulate maintain certain synthesized level of glutamate. |
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| 44:24 | you can understand that this imbalance can actually upset by upsetting glial cells, |
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| 44:31 | even neurons. If if for some glial glutamate transporters are not working. |
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| 44:39 | do you think may happen? You say well it will not synthesize glutamate |
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| 44:45 | I will say well it will also uptake glutamate from here because the transporter |
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| 44:51 | not working. So what will happen it going to be too much |
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| 44:55 | Too little or no change. So of these dynamics are very important and |
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| 45:04 | ourselves contribute to these dynamics. Post synaptic glutamate will bind to two |
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| 45:11 | types of glutamate receptors. The ones are channels are gonna tropic and the |
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| 45:17 | that are G protein coupled receptors, call them Meadowbrook tropic glutamate receptors. |
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| 45:22 | there was false of the post synaptic to the ion a tropic glutamate receptors |
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| 45:29 | plus this deep polarization is excitation but response to medical tropic widowmaker receptors could |
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| 45:36 | opposite of excitation because of the G coupled cascades and intracellular sequences that then |
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| 45:43 | . Following the activation of the medical leader made receptor tripartite synapse and this |
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| 45:51 | is very, very important. Of the cycling of glutamate is important, |
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| 45:57 | cycling of gaba is important transporters for also exist. So when gaba gets |
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| 46:04 | in the synaptic cleft, gaba gets taken back by neurons and the specific |
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| 46:11 | neuron will transport us to put it in. So when we discuss glutamate |
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| 46:21 | excitatory neural transmission. We distinguish between types of glutamate receptors one sure way |
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| 46:32 | which we know how to distinguish. is based on the chemistry or |
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| 46:38 | If you made chemistry of the brain glutamate will act through three types of |
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| 46:46 | A topic i on a tropical ultimate Tampa and M. D. |
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| 46:50 | And K. Nate. They are by the fact that each one subtype |
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| 46:56 | these ligament receptors will have their own chemical agonists such as amba. Such |
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| 47:04 | an M. D. A. kind in other words kind Nate will |
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| 47:08 | bind to an M. D. receptor And MD. A molecule will |
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| 47:13 | buy two amper receptors. So these all agonists. What are agonists and |
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| 47:22 | are antagonists? It's a very rough agonist is something that agonizes antagonist is |
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| 47:45 | that's what is a synonym for agonizing . Mm hmm, increase. |
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| 48:02 | Work it's a molecule called increase promote activity of something. So in this |
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| 48:11 | the agonist is gonna open the channel channel. Okay antagonists. It's something |
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| 48:25 | going to close the channel. So versus over. I don't know if |
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| 48:39 | gonna get it when we get to all. Yeah we may get to |
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| 48:43 | actually yeah it depends how this this goes here. So the pharmacology of |
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| 48:51 | pharmacology of dramaturgical receptors is first of . Ampatuan are often referred to as |
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| 49:00 | an M. D. A. they have similar dynamics similar kinetics which |
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| 49:07 | the opening and closing of the the speed the time at which it |
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| 49:12 | and closes the conductance how much of is going to conduct. So this |
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| 49:19 | here 20 P. S. Stands PICO cements each individual app or kind |
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| 49:28 | an M. D. A. Will conduct about 20 p. Cosima |
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| 49:33 | through them. An M. A receptor is different. It has |
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| 49:43 | kinetics But it also conducts 50 Casinos. So it's it's it's much |
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| 49:50 | conductance that is happening through an NBA as opposed to Apple channel. These |
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| 49:57 | have their own antagonists are also referred as blockers. Something that closes the |
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| 50:11 | again blocks the channel ample kin. will have their own antagonists just like |
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| 50:17 | had their own agonists. And that is C. N. Q. |
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| 50:21 | . And M. D. Will have its own antagonist which is |
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| 50:25 | PV or a P five an D. A. A lot of |
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| 50:30 | it's referred to as coincidence detector because is what happens when glutamate. This |
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| 50:39 | great molecules. Glutamate molecule. I'm this is the sodium molecule. This |
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| 50:46 | molecule is glutamate molecule here. When made molecule binds done in NBA channels |
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| 50:52 | opens none in MD. A channels and allow for the flux of mostly |
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| 50:59 | and potassium. But when glutamate binds an M. D. A channel |
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| 51:07 | not enough to open an M. . H. Other there are two |
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| 51:12 | things that have to happen that chemical we call glycerine and can inhibit their |
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| 51:19 | in the spinal cord is actually a factor for an M. D. |
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| 51:24 | receptors. And there has to be certain level of glycerine in the synopsis |
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| 51:29 | order for the glutamate to properly bind activate an M. D. A |
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| 51:35 | . But having glycerin is not going be enough. And it was glued |
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| 51:39 | me to open the receptor because this M. D. A receptor has |
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| 51:45 | block. So magnesium binding site is . In fact it has a couple |
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| 51:50 | magnesium binding sites And when glutamate and binds to this receptor it's not enough |
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| 51:57 | change its confirmation and to open it it's being blocked by magnesium ion sitting |
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| 52:04 | in the channel. And so what is the initial deep polarization of flux |
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| 52:10 | ions happens through amper channels. And is enough now to open an MD |
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| 52:16 | channels. That's why N. D. A receptors are referred to |
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| 52:19 | coincidence detectors. They have to coincidentally pre synaptic neurotransmitter release glutamate release and |
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| 52:28 | and also deep polarization that would come ample receptors. So ample receptors receptors |
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| 52:39 | responsible for the early phase of the polarization and N. M. |
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| 52:46 | A receptors are responsible for the late of the deep polarization. These synaptic |
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| 52:56 | that are produced by these temper and M. D. A. Yes |
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| 53:09 | . So this is the molecule level . Another molecule level by sodium will |
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| 53:17 | in sodium will flex in. Also will flex in. So all in |
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| 53:24 | channels are permeable to calcium and then will be flexing out. So when |
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| 53:35 | molecule when this blue to make molecule and then slicing through a factor for |
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| 53:44 | M. D. A receptor you first have an influx of sodium |
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| 53:50 | just build up influx of sodium and build up of positive charge on the |
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| 53:58 | membrane on the inside allows for this to get kicked out right now. |
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| 54:10 | after the initial deep polarization here now have a lot more deep polarization coming |
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| 54:17 | through an M. D. A . The way this looks is like |
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| 54:27 | . This is a membrane potential V. Let's say it's -65 million |
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| 54:36 | . Yeah glutamate that gets released here this point and you will generate and |
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| 54:45 | . P. S. B. is different from action potential. This |
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| 54:51 | a synaptic potential. Action potential is in the accents synaptic potentials are recorded |
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| 55:00 | the synopsis mhm. Synaptic potentials are . So you can have a snappy |
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| 55:08 | of this size. The smallest synoptic action potentials are all or none. |
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| 55:16 | if you produce another action potential and overlay them one over the other and |
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| 55:22 | can do 100 of them. It be all or not all the same |
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| 55:28 | all the time. E. P P s are not. And Tampa |
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| 55:35 | responsible for the early phase of G P S. D. And |
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| 55:42 | M. D. A receptors are for the late phase of the |
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| 55:54 | If you activate measurable tropic glutamate they're not channels and M. |
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| 56:01 | A receptor is an Iowa tropic receptor . Medical tropic receptor sir, linked |
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| 56:08 | G proteins and they can set off cascades that can be either promoting excitation |
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| 56:15 | inhibition depending on what extra cellular cascades them or follows. It's a medical |
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| 56:28 | signaling happens through transmitter binding to the protein coupled receptor and this G protein |
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| 56:37 | receptor gets activated. This G alpha GTP when it gets activated converted into |
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| 56:46 | and you have activated break up of subunits of the jew protium. One |
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| 56:53 | them can target and a factor protein is membrane bound and one of them |
|
| 57:00 | act on another affect the protein. . And they can also go downstream |
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| 57:08 | involved secondary messengers. So this is an example of basic motive operations of |
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| 57:15 | proteins. Okay. The molecule here binds it doesn't open a channel. |
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| 57:22 | it activates the jew brody in And these complexes will intracellular or membrane |
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| 57:29 | will have their protein defectors and other molecule defectives. Uh So this is |
|
| 57:41 | good diagram and I want to show where I've taken it from because I |
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| 57:46 | I'd like to give you an It's a lot of information today and |
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| 57:51 | think I'd like to give you an to to look at this description. |
|
| 57:59 | be happy to walk you through it but I'd like to take a little |
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| 58:02 | more than five or so minutes of time. If you go to your |
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| 58:10 | content materials under lecture reading materials, the glue dramaturgical mechanisms and Jasper's review |
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| 58:21 | epilepsy. It's written by really great school awesome progressive thinker Raymond Dingle |
|
| 58:34 | And this is where you will find description of this figure the trans membrane |
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| 58:42 | and crystal structure of the agonist binding B. D. Off the glue |
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| 58:48 | two subunit program. Don't. So what is this here and what are |
|
| 58:55 | going to discuss? And if you to again over the weekend, open |
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| 59:02 | up and read about it a little . It will tell you about the |
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| 59:06 | will go over the protein complex structure subunits with trans membrane subunits after glutamate |
|
| 59:17 | notice that one of them is only the side of plas mix side the |
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| 59:21 | versus gearbox will termine. I what means, what is the S one |
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| 59:28 | S two regions the binding regions. is the kind of molecule where does |
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| 59:32 | molecule fit into this big possible three puzzle of the receptor channel. What |
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| 59:39 | the flip flop region. So we'll these really cool things. We'll discuss |
|
| 59:47 | agonists bind on the am pocketed and receptors, right? And we will |
|
| 59:55 | discuss the concept of ah alle ist and Ortho static modulators. So today |
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| 60:07 | simple agonists antagonists. Most of you knew that Ortho hysteric versus Alistair |
|
| 60:13 | It's something that will talk about a of times. And with a couple |
|
| 60:17 | simple diagrams you'll know that forever the between the two and then we'll talk |
|
| 60:24 | how some of the al hysteric or hysteric modulators can be negative or positive |
|
| 60:33 | . So this is really good review we will focus as you can see |
|
| 60:38 | this article, we will focus really mostly these three. Uh Figure |
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| 60:45 | Figure two will be also discussing Figure because Figure four talks about the impairment |
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| 60:53 | reactively aosis and what may happen if have inflammation which leads to reactively aosis |
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| 61:02 | glia react to abnormal outside environment and they do that and how this can |
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| 61:09 | or either increase or in this case this case increase but also it can |
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| 61:16 | opposite decrease of production and regulation of been Okay so we learned here today |
|
| 61:23 | want to save your lectures and upload if you went to the U. |
|
| 61:27 | . Video points you saw that? also uploaded by accident undergraduate lecture from |
|
| 61:32 | year so I can leave it I can erase it. I just |
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| 61:36 | to not confuse anyone. I talked covid and infections of covid in that |
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| 61:43 | lecture through nasal cavity so I'll probably it just not to confuse. All |
|
| 61:50 | . Okay. All right well thank very much for being here. I |
|
| 61:55 | continue now. We will have our person meeting again on monday Today we |
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| 62:03 | eight people online. 4710 in So again almost the entire crew is |
|
| 62:11 | . Uh and you guys make your decision whether you're gonna be on zoom |
|
| 62:17 | in person. Okay. And by way your final exam date is also |
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| 62:23 | now so there's no longer a question in the exam date for the for |
|
| 62:28 | third midterm which is your final Yeah. Yeah. Yeah and it |
|
| 62:34 | be now and casa so you may be able to register, you can |
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| 62:37 | register for exams two weeks before but should be listed there the dates |
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| 62:42 | Yeah. Thank you |
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