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00:00 | Good morning. Welcome back. It's lecture 13 of neuroscience. And you |
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00:08 | more than halfway through the semester and than halfway through covering all of the |
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00:15 | that we intend to cover in this . Uh If everything goes smoothly with |
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00:21 | force in the world in general, a reminder, we have been talking |
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00:27 | neural internal submission. We are gonna talking about neural transmission today and begin |
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00:35 | about some of the major parts of C MS. We'll continue talking about |
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00:41 | also on Wednesday and I'm waiting to back from Casa for their confirmation. |
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00:46 | was actually trying to check my email too about your quiz on Friday and |
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00:52 | can give my email to update for second. So let's see, not |
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00:58 | , but maybe later today, it be available and you'll see it if |
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01:04 | not. And there's some issue with will communicate over email before next |
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01:10 | but most likely it will be there today. Ok. So neural |
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01:18 | we covered a lot of ground, lot of information, a lot of |
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01:22 | molecules and we ended here, we by talking about excitatory optic potentials and |
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01:34 | these excitatory synoptic potentials are generated when binds to A and, and MD |
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01:42 | receptors. And we started talking about differences between these two subtypes of ionotropic |
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01:53 | have made receptor channels. And just remind you where we all are |
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02:00 | Now, when we talked about uh , we talked about this tripartite |
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02:10 | And we said that for glutamate, it gets released, it will target |
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02:16 | and metabotropic receptors. In the C S, it will get transported back |
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02:21 | neuronal transporters, but it will also transported by glial transporters into glia. |
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02:27 | , glia is a part of what call this tripartite synapse where essentially takes |
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02:31 | glutamate, turns it into glutamine and it back to neurons, the pre |
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02:37 | neurons. So they can synthesize glutamate of it again. So here, |
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02:42 | , the third part of the synapse intricately controlling this excitatory signaling. You |
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02:50 | transport for glutamate, you have transport glia for glutamate. We talked about |
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02:57 | . So, endogenous agonist for and A and age receptor is glutamate. |
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03:04 | a molecule that gets produced in the . And then we have exogenous agonists |
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03:11 | are chemicals by which these different subtypes tropic. And the can be |
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03:20 | They also have their distinctive antagonists. talked about that when glutamate binds the |
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03:30 | receptors, ample receptors open immediately and are responsible for the initial phase of |
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03:38 | E P S P and, and A receptors have a magnesium block. |
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03:44 | the only way that this magnesium block alleviated if the membrane depolarizes from resting |
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03:51 | potential into more positive potentials, which for magnesium to leave and for an |
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03:59 | B A receptor channel to open a of the conductance of sodium calcium inside |
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04:05 | potassium to the outside. So if look at that E P S P |
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04:09 | general, this early phase of E S P is primarily due to alpha |
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04:16 | . And this late phase of E S B is due to an MD |
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04:21 | receptor. Thanks, They're both ionotropic the sense that they both conduct on |
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04:31 | . Now, Alpa will have uh 20 PICO of conductance and MD a |
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04:41 | will have 50 PICO of conducts. that tells you that this is a |
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04:47 | uh once you open an MD A , it can conduct a lot more |
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04:52 | that channel. But you have to it an MD A receptor and Aina |
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05:00 | channels that have their own blockers or . So Aina will get blocked by |
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05:07 | N Q X and then MD A will get selectively blocked by A PV |
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05:13 | A P five. An MD A is referred to as coincident detector. |
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05:20 | in order for it to open and conducting, it needs to detect the |
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05:26 | synoptic neurotransmitter release, which is And it also needs to detect the |
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05:34 | optically. So that it can alleviate block. So it is very well |
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05:41 | in M B A receptor in having ability to bind a presynaptic activity with |
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05:47 | , with a significant postsynaptic activity so it engages and opens the channel. |
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05:55 | , glutamate in the C N S also have glycine as a co |
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06:02 | So in the spinal cord, you that glycine is one of the major |
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06:07 | neuro transmitters in the spinal cord. in the C N S, glycine |
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06:14 | a co factor, which means that glycine also in the synopsis and it |
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06:19 | to bind together with glutamate in order this channel to be really effective open |
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06:25 | both and regulated properly by glutamate and synaptic depolarization. So the other difference |
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06:35 | that all the M B A sufferer allow for sodium and calcium to come |
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06:42 | calcium doesn't contribute that much to change the numbering potential as it is contributing |
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06:48 | the intercellular processes that it can set sally. But it does flock through |
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06:56 | MD A receptor channels of potassium e . Now, only certain or not |
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07:03 | MD A receptor channels, only some those aut channels will be permeable to |
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07:09 | , but they're all permeable to sodium potassium. So there's a selectivity here |
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07:14 | some channels aut channels are selected just sodium influx without calcium. And we'll |
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07:21 | that why in a second. obviously, since alpha receptor channel is |
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07:28 | first, it has fast kinetics is for the early phase of the E |
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07:34 | S P. And then MD A responsible for the late or the late |
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07:39 | of the late phase of the E S P. Both channels are on |
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07:45 | , not to be confused with the signaling. And we'll look at some |
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07:48 | the examples of metabotropic glutamate receptor that be linked to G coin complexes. |
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07:56 | also these receptor channels is the rule . Later, you'll see today, |
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08:02 | as well. They have multiple binding for different substances. So, |
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08:08 | endogenous substances, but also exogenous agonous antagonist also binding sides for ions |
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08:17 | magnesium, for example. Uh it also is a target for certain |
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08:26 | narcotics or certain illicit drugs like PC , also referred to as angel dust |
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08:32 | a lot of times a single use repeated use of that drug has very |
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08:39 | interaction with an MD A receptor that have very long lasting changes. Because |
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08:44 | MD A receptor is a coincident An MD A receptor is perfectly positioned |
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08:50 | mediating the plasticity or the communication between synoptic and posy tic cells. A |
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08:56 | of these molecules that are endogenous are binding properties where they may bind to |
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09:03 | receptor and they may dissociate from that a certain period of time later. |
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09:09 | a lot of synthetic and illicit drugs have much stronger binding properties to these |
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09:14 | . They may not dissociate and fully this receptors or alter the function of |
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09:19 | receptors for days, sometimes weeks. that can lead in the case of |
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09:25 | P S to psychosis uh to bouts acu schizophrenia and even permanent or chronic |
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09:33 | dysfunctions mental conditions like schizophrenia and So, it's a very important |
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09:40 | But when that receptor is affected by wrong substances, it can also induce |
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09:47 | long lasting changes versus the positive long changes that are just normal brain functioning |
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09:53 | plasticity. So recall that in the section of this course, we talked |
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09:58 | this concept of voltage clown and we that voltage clown, what it allows |
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10:03 | to do, it allows us to the numbering potential at a desired |
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10:08 | your desired value. It's very valuable voltage clamp allows us to study to |
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10:15 | inward and outward currents And allows us look at the in the case of |
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10:22 | ions such as sodium and potassium allowed to look at the ionic or reversal |
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10:30 | for an individual ion such as right? And we saw that |
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10:37 | for example, reversal potential was -80 reversal potential was positive 55. |
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10:45 | we can perform equivalent type of experiments the voltage clamp. But now we're |
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10:51 | at these receptor channels that are permeable both sodium potassium, sodium, calcium |
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11:00 | potassium in the case of an MD receptor. So we do a voltage |
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11:05 | and in this experiment. It's two in the first conditions. It's physiological |
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11:13 | of magnesium and the extracellular solution. 1.2 milli molar on the left on |
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11:20 | right, it's an experimental condition in magnesium has been removed from extracellular |
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11:27 | There's zero magnesium and extracellular solution. that magnesium has a binding site, |
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11:34 | MD A receptor and it can block MD A receptor by binding to the |
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11:41 | and it can only lead that receptor there is depolarization. So first in |
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11:47 | physiological level, also of magnesium at 60. When we apply glutamate, |
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11:53 | we have isolated an MD A receptor at minus 60. We see very |
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11:59 | MD A receptor burns and that's because is no depolarization. So, glutamate |
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12:03 | not enough to start the current fluxing these. So you're seeing almost a |
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12:08 | line here. This is electro physiological voltage flat at minus 60. The |
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12:14 | the start you're starting to see foxes happens at zero millivolts. This is |
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12:22 | instead of ionic, what we have is a reversal potential. So in |
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12:31 | case, it's a reversal potential e at which potential. Basically there's no |
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12:39 | of cars in either conditions on the of the right at zero millivolts. |
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12:45 | when I, when we, when looked at the uh the I V |
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12:51 | for potassium and we said that this if you, if you look down |
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12:57 | , OK. This is uh this all um outward current and this is |
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13:13 | excellent, let's start with this, looked at the I V plot. |
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13:19 | this is the current and this is voltage. And we, when we |
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13:24 | at the potassium, we said that minus 80 millivolts, we have a |
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13:30 | potential for potassium. In this it's equilibrium potential for potassium. |
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13:36 | Because below minus 80 millivolts, potassium going inward. I just uh I |
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13:44 | have miswritten these two. And here this side where the current is positive |
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13:53 | , the current is outward. So remember when you depolarize the cell potassium |
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13:59 | be fluxing outward. So the equilibrium for potassium was -80. Now, |
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14:07 | looking at ions fluxing through an MD receptor channel, multiple islands and they |
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14:16 | a reversal potential. So we cannot it's equilibrium potential because equilibrium potential is |
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14:21 | single island only the reversal potential of , currents fluxing inwardly. So here |
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14:30 | fluxing inwardly and here the reverse. here you can see the currents of |
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14:36 | and outward. And so this is reversal potential value. When MD A |
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14:42 | channel is zero millivolts, we'll look it in, in in more detail |
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14:46 | a second. So essentially E P P and a potential in the neuromuscular |
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14:57 | , which is mediated by nicotinic acetylcholine and E P SPS, which are |
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15:05 | by alpha and an MD A receptor . They all have a reversal potential |
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15:15 | zero millivolts And you'll see that. now what's the difference between left and |
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15:22 | and the right, we removed we now have glutamate in the presence |
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15:27 | glutamate and -16, we've just proven if you remove magnesium and MD a |
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15:33 | channels will be open at negative So this is the point of this |
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15:38 | but to prove this experiment, you to use voltage clamp, you have |
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15:42 | have a condition in which you are . In this case, the amount |
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15:46 | magnesium. And you prove that it's magnesium that's blocking an MD A |
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15:53 | , uh these normal physiological concentrations and you remove it, you can actually |
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15:57 | an MD A receptor activation here. let's go back to. So some |
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16:03 | the drawings that I did before and let's go and look at this uh |
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16:08 | here. In this case, we a voltage clamp -80 -40 positive |
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16:17 | We have this dash here. This small dash here which is an artifact |
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16:24 | . It's let's say glutamate release. . Following that we are recording |
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16:31 | So these are inward currents and these outward currents. Now, when you |
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16:44 | and you produce this response, you're at least two dash lines. The |
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16:50 | dash line is measuring the response about milliseconds following stimulation. So you're |
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16:56 | really measuring this peak early current And the second dash line is taking |
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17:02 | measurement about 2030 milliseconds following the stimulus the same traces, these electrophysiological |
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17:13 | And so when we climbed at -80 plus 20 and measure an early |
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17:21 | that early component is the nom an component. And we can see that |
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17:26 | early non MD A component has this ID plot which is the triangles. |
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17:33 | we can see that this alpha which the non and MD A component has |
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17:39 | reversal potential at zero millis when we the measurements at the late component |
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17:50 | 30 milliseconds later these in different holding And this is current. So you |
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17:58 | , I so these are the closed and these are the measurements of |
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18:04 | There's barely any current, you're measuring change from here to here to change |
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18:12 | here to here. OK. At X Y. How far away is |
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18:17 | trace from this? How far away the trace from this is how you |
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18:22 | the altitude of, of the current anything or? Uh or or? |
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18:28 | it turns out that an M B is the closed circles. It has |
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18:31 | nonlinear M V P with the reversal of zero M vats. And these |
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18:37 | the closed circles and the MD A is responsible for this laid and MD |
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18:43 | receptor component card, which is pictured as the blue area under the |
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18:50 | And the final experiment here is that add a PV where you have these |
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18:56 | circles, late current is remaining after added a PV. And you do |
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19:04 | measurements again. So you added an MD, a blocker specific blocker |
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19:10 | an MD A and you can repeat measurements for ample receptor and guess |
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19:16 | It's not going to affect ample receptor so close circle uh closed uh triangles |
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19:23 | open triangles. It, it, doesn't matter in the presence of an |
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19:27 | A receptor or blocker or an absence that blocker. It still is a |
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19:33 | component. It doesn't affect it because tells you it's a specific blocker, |
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19:40 | ? A PV specific to an MD or sock. Now, when you |
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19:47 | the current in the presence of A , you get this curve here that |
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19:53 | the open circles and it's essentially blocked zero current. There is some |
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20:00 | but it's essentially blocked to zero. a current. So that tells you |
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20:06 | you can block this la component with PV, that an MD A receptor |
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20:12 | responsible for that lead component. And an MD A receptor channel I V |
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20:17 | is nonlinear just compared to a, have a reversal potential of zero M |
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20:24 | . And so does that potential in neuromuscular junction that's uh mediated by nico |
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20:32 | cole receptors. So some ample receptors indicated are permeable to calcium but not |
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20:40 | . So why are some permeable and are not? So when we look |
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20:46 | the structure And this is remember we transmembrane segments. This is transmembrane |
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20:53 | M one and two and three and . Yeah. Part of the subunit |
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21:00 | is comprised of amino acids as building with a protein channel. Everybody with |
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21:14 | . No, remember this, you sub units and then you have M |
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21:23 | M two M three M four. we studied voltage gated sodium channels, |
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21:27 | had transforming segments as one as two is four. So it's a little |
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21:32 | for Ligo G and ion channels. that was an example of nicotine uh |
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21:37 | codeine receptor. So M one M M three M four and you take |
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21:41 | sequence that contains Q or glutamine. remember this is a very complex three |
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21:50 | protein with a very long amino acid . But if that sequence contains |
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21:57 | you apply glutamate, you get sodium and you get calcium cars, but |
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22:04 | versions of apertures will have arginine where uh where that glutamine iss Q, |
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22:13 | is substituted with arginine. And there basically variations so that they will have |
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22:19 | and in the presence of that arginine amino acid. Now you apply glutamate |
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22:24 | you still have sodium currents, but don't have any calcium currents. So |
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22:31 | a single amino acid in this really structure in a single trans numbering segment |
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22:37 | significant, whether that channel allows for flux of calcium or not. |
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22:42 | calcium doesn't contribute that much to the and potential change, the fast number |
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22:47 | potential change. Like we're talking about E P SPS or action potentials and |
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22:53 | , but it contributes to intracellular signaling activating calcium binding molecules and calcium homo |
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23:01 | and so on or or development. early synopsis in neurons, it's early |
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23:11 | stage of synopsis will contain only an A receptors. So they will not |
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23:16 | ample receptors. So that's not very if you release glutamate and there is |
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23:22 | ample receptors. That means there is synaptic depolarization. That means that if |
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23:28 | is released, it's going to be . And they're referred to as silence |
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23:34 | for the ones that express only in A receptor. And then later in |
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23:40 | , a receptors get expressed in this . And so there are rearrangements that |
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23:45 | developmental that are development dependent, but are also rearrangements as part of the |
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23:55 | , we call activity dependent proper processes can rearrange a number of the sufferer |
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24:00 | and the plasma membrane. And such other thing is the subunit compositions are |
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24:06 | subunits that comprise these protein channels. can be different subtypes. Here, |
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24:13 | go back again to the nicotinic acetylcholine . And here you have alpha two |
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24:23 | , beta gamma delta of unus that this receptor protein channel. OK. |
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24:31 | if we go back to an MD , they're just called something a little |
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24:37 | . They're called N R two A R2B subunits. But as a part |
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24:44 | the development and sometimes a part of activity which is plasticity processes, there |
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24:51 | be a rearrangement in the composition of subunits within an MD A receptor where |
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24:59 | some point there's a greater ratio of R two A to an R two |
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25:03 | and then it could switch greater ratio an R two B to an R |
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25:08 | A or equal ratio of the two types of subunits that are a part |
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25:14 | this with up channel cellular location. activity dependence is changes with age and |
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25:24 | . A receptors moves fast. So lot of receptor channels, as you |
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25:32 | are expressed in the synoptic densities. a very specialized area confined the synapse |
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25:40 | synoptic densities. But there are extra spaces in the membrane that goes beyond |
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25:48 | synapse space. And you can actually apa receptors through plasma membrane from extra |
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25:56 | spaces into the synapse. You can that as a part of the |
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26:01 | you can do that as a part the demand. So let's say there |
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26:06 | a lot of activity, there's a of glutamate release and you need to |
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26:11 | the synapse. And one way in you can change the efficacy or the |
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26:16 | of the synapse, which we refer as plasticity. One way in which |
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26:21 | can do it is by insertion of receptors such as glutamate output receptor |
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26:28 | So that s Sino becomes even more at depolarizing, even more effective at |
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26:33 | an MD A receptors. And if have significant amount of activity, it |
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26:41 | cause long term plasticity to abbreviate as T P. So long term plasticity |
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26:49 | likens to long term memory. things that you do rehearse repeat many |
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26:55 | , get ingrained in your head and hard to forget him, Things that |
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27:01 | do once or twice, remember a number and then you forget it 10 |
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27:04 | later, short term memory, things that. Things that you study for |
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27:08 | test and you forget over spring short term memory. You know, |
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27:13 | you're gonna have to repeat it Hopefully, it's gonna be a long-term |
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27:16 | . So you can still repeat it after the course is finished. |
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27:20 | and MD A receptors and the cycling import of additional glutamate receptor channels and |
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27:27 | are all very important cellular substrates or processes that underlie learning and memory metabotropic |
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27:37 | receptors. This is an example of glutamate receptor that is linked to gate |
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27:44 | that interacts with a molecule called P two. And with the fossil I |
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27:51 | , it converts that P IP two IP three or no trios and an |
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27:58 | trios can bind to calcium channel. these are basically IP three regulated calcium |
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28:07 | and smooth endoplasm reticulum and S er loaded with calcium and stimulation and opening |
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28:16 | this calcium channel can now provide a of calcium from internal vesicular stores |
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28:24 | And the smooth endoplasm reticulum into the freely floating or what we call cytoplasmic |
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28:32 | calcium is very tightly regulated when there's of calcium. If it starts interacting |
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28:39 | molecules, secondary messengers, kis and like that, it's tightly regulated. |
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28:45 | so if you stimulate even more of calcium, you have another way for |
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28:51 | cells to access calcium in the cytoplasm releasing it through from the, the |
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28:57 | endoplasm reticulum. You can see that of this molecule causes a divergence in |
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29:03 | molecular pathway. IP three stimulates the on smooth endoplasm reticulum and diacylglycerol or |
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29:13 | A G remains membrane associated in It interacts with protein kinase C which |
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29:20 | a kinase. And this also says calsci can interact with calci module cave |
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29:26 | or CA KIS. So what KS is kis for spate channels. So |
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29:36 | can phosphor channels, they can add P 04 group and that's and phospho |
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29:43 | de phosphorylation or will chew up the 04 group. A lot of times |
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29:51 | can cause longer lasting effects, can the channels and dephosphorylation can impede with |
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30:00 | with activation of these channels. So , there is a regulation of these |
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30:07 | and phosphate AIS intercellular as well and will influence a lot of what has |
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30:13 | in gods stream from metabotropic. In case, glug metabotropic signaling, there's |
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30:20 | different metabotropic glutamate receptors, but they're activated by glutamate and linked to G |
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30:27 | complexes. All right. So now moving into inhibition, we understand a |
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30:35 | about excitation A and MD A agonous , early lady P S P magnesium |
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30:45 | and also substances that bind uh to MD A receptor. Now, when |
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30:51 | talk about IP SPS as a E P S P poop is exci |
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31:00 | pontic potential or depolarization, right? an IP S P, I'm trying |
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31:07 | find another diagram but maybe it's not . I'm just gonna have to drive |
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31:14 | P S P is a depolarization and S P is a hyper polarization inhibitory |
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31:25 | potential. So you get inhibitory postsynaptic when inhibitory neurons release gabba, this |
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31:34 | gabba, a receptor channel. Gaba gamma a receptor channel which is permeable |
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31:45 | chloride and chloride influxes inside the So negative charge chloride negatively charged ion |
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31:55 | inside the cell will cause a hyper . This is E P S P |
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32:03 | is depolarization and IP S B will hyper polarization. So chloride coming in |
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32:10 | the E P SPS, you had coming in at first, right? |
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32:13 | that was depolarization and the IP SPS chloride coming in. So it's hyper |
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32:20 | . Now notice that this receptor channel has a lot of different binding |
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32:28 | Yeah, obviously opens the channel. is it agonist or antagonist? I |
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32:37 | , I guess. And so are molecules? So ethanol, alcohol binds |
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32:46 | Gaba a receptor channel, benzodiazepines, which are classic antiepileptic anti seizure |
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33:01 | benzodiazepines that find their way into popular as Bezos barbiturates and there are |
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33:13 | So all of these molecules are like and they have to find the correct |
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33:20 | . And so S N O will its key hole in the Gaba A |
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33:25 | not in the glutamate, not in M B A to. So a |
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33:32 | of these molecules have their distinct So you can imagine that this receptor |
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33:38 | is like a door. You can that door, the channel is |
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33:43 | you can close that door, but not simple. The door has multiple |
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33:48 | on it and some locks can open and close it, some locks just |
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33:54 | it a little bit more or keep open longer, but they don't have |
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33:59 | ability on themselves to open. So are different variations of agonous and |
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34:05 | And that's why I was saying that of the molecules that are uh uh |
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34:12 | induce chronic or unwanted chronic effects are ones that are synthesized. And we |
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34:18 | know precise interactions with the receptors or have very strong interactions with different |
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34:25 | So, Benzodiazepines will increase inhibition, will increase inhibition. Barbi nesters will |
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34:33 | inhibition. The people that are taking is medication for epilepsy seizures. They |
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34:41 | often report that they feel drunk because activates gale a receptor channel. The |
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34:48 | that ethanol will be activated. So it's Monday. So we're gonna, |
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34:54 | talk about what happens during happy So that's when I leave it for |
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35:00 | or maybe a review later this OK. So now that's Gabba A |
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35:08 | we also have Gaba B and this what's a little bit different about IP |
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35:14 | versus I E E E P SPS that this early depolarization, this early |
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35:23 | is Gabba A, it's chloride, . Chloride coming in and this la |
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35:34 | is Gabba B and it's potassium going . Gabba B is a metabotropic Gaba |
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35:48 | channel. The poop is linked to channels. So when it gets |
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35:55 | this receptor protein complex opens up potassium and the flux of potassium inside the |
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36:04 | outside the cell from inside to the of the cell hyperpolarize the membrane potential |
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36:10 | further. So this early component of S P's Gamba A really. And |
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36:18 | late component is the right and that through tropic activation of G podium complex |
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36:31 | opening off a synoptic potassium channel. Gabba B with separate complexes can block |
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36:41 | of calcium. So we'll look at examples in the second. But now |
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36:50 | happens typically, we'll talk about the diagram in a second. What happens |
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36:56 | is that you will have excitation. is an E P S P. |
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37:01 | if you stimulate the fibers and a of times when you do these |
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37:08 | you may have different projections from the . You're recording here with an |
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37:14 | A lot of these are gonna be or glutamate projections and some of them |
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37:21 | gonna be inhibitory. And typically after stimulate a collection of fibers, you're |
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37:28 | stimulate excitatory and inhibitory. That means going to release a lot of |
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37:33 | But you're also gonna release some gaba this posy tic neuron. And all |
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37:38 | these synapses are targeting this postsynaptic So what is common to see is |
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37:45 | E P S P that is followed IP S P. So this is |
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37:51 | P S P, the excitation that followed by IP S P. So |
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37:57 | engage excitation. And what happens is inhibition keeps this excitation in check |
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38:06 | and if you apply by Culin. there's a lot of information on |
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38:11 | This is actually uh experiments that I over uh 10 years ago in journal |
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38:19 | Neurophysiology by Curricula is a gabba a antagonist. So all of these substances |
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38:26 | agonists, they will allow for more of chloride, more hyper fluor. |
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38:33 | where they sedative there is increase then we block gamma A. So |
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38:41 | is trace number one E P S followed by IP S P and we |
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38:46 | inhibition and this is trace number Now we have this unchecked excitation, |
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38:51 | large depolarization and action potentials even produced . So it's that that experiment |
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38:58 | is in the visual system is very uh set of experiments that really illustrate |
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39:05 | tightly inhibition controls excitation. And if block inhibition of bicuculline, this excitation |
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39:13 | massive. Uh I recall it a of times runaway excitation, it becomes |
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39:19 | strong and large in amplitude and spreads the tissue as well. OK. |
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39:27 | every section, I say that this a great diagram where you should print |
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39:31 | for yourself in a separate page or know, have a digital copy of |
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|
39:36 | slide to take it apart in digital , whatever you wanna do and all |
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39:40 | skills you have to use and put of the information here about excitation inhibition |
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|
39:50 | this summarizes a lot about what we about excitation and inhibition. Um recall |
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39:58 | neurons will have both excited and inhibitory targeting them. So the response of |
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40:06 | neuron will depend on the subset of receptors it has, whether it has |
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40:10 | A only or Gala A gappa whether it has a lot of APA |
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40:15 | an MD A or little APA and on. Now, what is happening |
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40:21 | in this diagram is a lot, you have a key here and that |
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40:28 | shows you the major players. Now talk about what exactly is happening. |
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40:33 | first of all, we have gaba presynaptic terminal and glutamate, releasing presynaptic |
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40:42 | . That means that this is an cell that's starting this synoptic neuron. |
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40:47 | this is an excitatory cell that's targeting synoptic neuron. So when Gaba gets |
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40:55 | from this inhibitory synapse here it binds gabba A receptors, chloride influxes and |
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41:02 | get IP S P hyper polarization nearby have gabba B receptors, binding of |
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41:11 | to gabber B receptors will open potassium and cause more hyper polarization. |
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41:18 | Gaa A gala B also the inhibitory have Gaba B that are expressed presyn |
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41:32 | . And when there is Gaba that released by the inhibitor synapse, these |
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41:39 | are Gabba B auto receptors because they're the same synapses released as gabba, |
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41:46 | activation of these Gabba B O receptors regulate and close calcium channels, voltage-gated |
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|
41:59 | channel. So calcium is necessary or binding and release of neurotransmitter. So |
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42:08 | is if there's Gaba, it can inhibition synoptic gabba A Gabba B IP |
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42:16 | , but it can also self inhibit own release by regulating calcium influx presyn |
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42:25 | nearby. We have this excitatory Obviously, when glutamate gets released, |
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42:31 | gonna activate APA first and then an A receptor is but an MD A |
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|
42:36 | shown here in yellow are typically a source of calcium influx. And when |
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|
42:42 | comes in oop, it can interact calcium molecules such as calcium, co |
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|
42:51 | kis camus. And these Aes on own can affect potassium channels posy or |
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43:02 | affect gal B receptors optically which will potassium channels openly. Potassium channels will |
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|
43:13 | hyper polarization and hyper polarization is not . Hyper polarization is going to be |
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|
43:22 | an MD A receptor function. So , Gaba B actually has nothing to |
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|
43:30 | with inhibitory synapse. This is in excitatory synapse but is located synaptic and |
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|
43:39 | regulating potassium, it can cause hyper synoptic through the cellular mechanisms. There's |
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|
43:48 | Gaba released here. Now, the way in which Gabba can control presynaptic |
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|
43:55 | release is that glutamate synapses have Galba heteros. And if there is a |
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44:04 | of Gaba being released here, this is going to spill over into adjacent |
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44:11 | spaces. And if it binds to B receptors on this pre synoptic excitatory |
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44:22 | , it will block calcium influx and will regulate the release of glutamine. |
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|
44:29 | , Gabba B receptors are expressed on inhibitor and excitatory on the inhibitory |
|
|
44:36 | They're called auto receptors on the excitatory . They're called hetero receptors. But |
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|
44:43 | both cases, Gabba can presynaptic regulate glutamate or Gaba release its own |
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|
44:53 | So this is reminiscent actually of the signaling. If you remember, maybe |
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|
45:00 | have this in this presentation here And then the cannabinoid signaling, we |
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|
45:05 | retrograde signaling activation of CD receptors which down calcium channels, blocked calcium channel |
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45:16 | and controlled both the excitation and So now you have Gabba B receptor |
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|
45:27 | does the same. So there's redundancy ? There's multiple ways in which you |
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|
45:34 | control pre synoptic inhibitory or exci neurotransmitter , you can do it through Gabba |
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|
45:41 | , you can do it through cannabinoid presynaptic. But it's a very different |
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|
45:47 | , very different molecules. But they all converge on the same presynaptic calcium |
|
|
45:54 | . You can do it in, other ways through a demo receptor signaling |
|
|
46:00 | . So there's multiple ways in which will start affecting the same calcium |
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|
46:06 | In the end, when you affect tic calcium channels, you're regulating neurotransmitter |
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|
46:12 | , excited to inhibit their neurotransmitter, G pros are different than structure. |
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46:20 | and they're different in such a way they're coupled to uh G part coupled |
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|
46:25 | . So which are seven trans member segments, acetylcholine glutamate gaba, |
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|
46:33 | dopamine orne and coin cannabinoids A T . They all will act through metabotropic |
|
|
46:41 | receptors. In addition, acetylcholine glutamate Gaba will act through ionotropic receptors. |
|
|
46:49 | , acetycholine nicotinic glutamate A MD A a their ionotropic, but then they |
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|
46:58 | have their distinct metabotropic muscarinic, different of subtypes of receptors that are metabotropic |
|
|
47:09 | one through probably 14 or 15. now, it grows every year. |
|
|
47:15 | subtypes of these channels get discovered and functions get precisely described and distinguished from |
|
|
47:21 | channels. So this shows you again more time. This is a lion |
|
|
47:26 | receptor channel, nicotinic. Remember we uh two acetylcholine molecules to bind to |
|
|
47:33 | receptor in order to open the OK. That's nicotinic, you will |
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|
47:39 | M one and two and three and , you will have some of the |
|
|
47:44 | replication, uh very similar sequences of acids and gabba, a alpha |
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|
47:52 | gabba a, a beta one but they will express them one and |
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|
47:58 | and three and four Coline Gaba glycine uh glutamate um receptor channels. In |
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|
48:06 | case. And the composition of these again, for nicotinic, it's alpha |
|
|
48:12 | . And then the A receptor, talk about N R two A and |
|
|
48:15 | two B. They're called little different all of these channels. OK. |
|
|
48:21 | there's a lot of information on the . But what do you need to |
|
|
48:25 | for the quiz or the task acetyl ? You have to know nicotinic and |
|
|
48:30 | , of course, nicotine and That's easy as agonous nicotinic muscarinic. |
|
|
48:37 | you cannot say that nicotine is an or muscarinic. That would be grammatically |
|
|
48:43 | . I'm just kidding. But uh would be incorrect antagonist, Cura and |
|
|
48:52 | Norine. You should know that alpha beta receptors have this opposing action, |
|
|
48:58 | atropic action of push pull mechanism. activating through G S another activating through |
|
|
49:05 | I converging on cyclic A P. is pushing the production beta AIC, |
|
|
49:11 | alpha Denner is pulling away the production cyclic A P made A NBA A |
|
|
49:18 | MD AC N A P five for , Gaba Gabo A Gabo B and |
|
|
49:24 | is an antagonist for Gale A because saw that really nice. Uh |
|
|
49:29 | Just a short time ago. A P acts through a type receptors and |
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|
49:39 | two X receptors. A type receptors also the target of the denison. |
|
|
49:45 | , agonist is a dennison or a receptors. A T P will bind |
|
|
49:52 | those receptors that which is a, endogenous substance. It goes up at |
|
|
49:57 | and it blocks the release of calcium glutamate synopsis. So it slows our |
|
|
50:01 | activity down and then caffeine is an for denine receptors. And caffeine allows |
|
|
50:12 | calcium channels to, to function. it blocks the denine receptor function allows |
|
|
50:17 | calcium channels to open and stimulates glutamate . So it encourages kind of your |
|
|
50:23 | to wake up every morning. There's of coffee there, by the way |
|
|
50:29 | of caffeine uh gamma A receptor you can play games. So like |
|
|
50:36 | beta gamma delta row, but it's just games structure equals function, which |
|
|
50:43 | that if you change the the subunit , delta gamba versus uh gamma gamma |
|
|
50:52 | subunit, the current flux may have properties. There may be more current |
|
|
51:00 | through that. Uh g acceptor, chloride coming in, maybe it's open |
|
|
51:06 | . So it's not fluxing more but it's staying open longer and it's |
|
|
51:12 | more chloride to come in. But conductance is the same and you have |
|
|
51:17 | iterations of these subunits which basically dictate different subtypes of metabotropic receptor channels that |
|
|
51:25 | saw here. M one M two three and four and so on, |
|
|
51:30 | have a significant level of amplification and chemical synopsis. So when you have |
|
|
51:38 | or cellular signaling, you have binding that molecule to the receptor, it's |
|
|
51:44 | a channel, but it can be to several G part complexes. |
|
|
51:49 | depending on the binding properties of that , the receptor, the time, |
|
|
51:54 | duration of time that it stays bound to that molecule or where it is |
|
|
52:01 | it affects the function and interactions with Gin complex. Maybe you can activate |
|
|
52:06 | G complexes, maybe you can activate G per complexes. One can cause |
|
|
52:12 | effect on multiple effector systems or a cyclo conversion of A T P multiple |
|
|
52:19 | T P S into cyclic A MP cyclic A MP can now affect multiple |
|
|
52:26 | kis and those K one K can multiple channels. So from one |
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|
52:32 | one G protein uh coupled receptor you have amplification um of the |
|
|
52:42 | Now you have amplification, you also divergence in the sense of neurotransmitter, |
|
|
52:47 | same neurotransmitter combined to subtype one, type two, subtype three. So |
|
|
52:52 | example, Norine alpha data, sub one, sub type two, sub |
|
|
52:58 | two will diverge and actually interact with effective systems like y whatever the kind |
|
|
53:06 | is possible cases of molecules you also convergence. So three different transmitters. |
|
|
53:15 | three different receptors would be converged on same effector system Examples, three different |
|
|
53:23 | and cannabinoids. A. Dano gabba or gabba neurotransmitter, different receptors. |
|
|
53:33 | all converge on a factor system, channels. Now, you also have |
|
|
53:42 | and parallel streams. So you have . These neurotransmitters can have parallel streams |
|
|
53:51 | a one receptor and a two receptor parallel will converge on the same factor |
|
|
53:58 | in parallel. They may also diverge , you can access, for |
|
|
54:05 | this effect to three Here by either a, a one receptor factor three |
|
|
54:12 | BB receptor factor three. So even you lost a neurotransmitter, you can |
|
|
54:21 | get to the same factor through these divergence um mechanisms. And there's a |
|
|
54:30 | level of redundancy so that your signaling cellular level is protected. If you |
|
|
54:37 | a chemical, if you lose a type of the receptor potent with this |
|
|
54:49 | material, we're gonna remind ourselves that studying the brain and that all of |
|
|
54:55 | chemicals, all of these molecules we're , they're part of these networks, |
|
|
55:01 | part of these structures, these networks these structures that have their distinct |
|
|
55:09 | This is the brain. So the to scale. So a really small |
|
|
55:15 | like rab rabbit, cat brains just few centimeters in size, the human |
|
|
55:24 | , the dolphin brain, the largest I think are in um elephants. |
|
|
55:32 | if we listened very diligently to phrenologists remember the science of phonology, one |
|
|
55:40 | their arguments that um other things being size is a determinant of the power |
|
|
55:48 | the organ. Like the size of muscle is determinant how much of the |
|
|
55:52 | it can lift. So dolphins should with their bigger brains and bigger skulls |
|
|
56:03 | be on top of the food And I always make this argument if |
|
|
56:08 | in the water, they are, you're not in the boat and you're |
|
|
56:13 | the water, do you hope that, that the dolphin are, |
|
|
56:17 | gonna help you in some way, be much smarter and better survival in |
|
|
56:22 | marine environment using different sensory cues and physical um and mental abilities uh by |
|
|
56:31 | same virtue. Um Maybe elephants rule world, then we should go back |
|
|
56:39 | this ancient painting of elephants holding the on their backs uh because they would |
|
|
56:47 | the biggest bridge. Now, when look at those brains not to |
|
|
56:52 | you also see similarities in structures. see differences in in structures and one |
|
|
56:58 | difference is a lot of the lower , organisms, animals like rat and |
|
|
57:06 | , their brain surfaces are relatively There's even a saying in, in |
|
|
57:11 | , the lizard brain or a smooth , which means it doesn't have much |
|
|
57:16 | . You know, you can see you have a lot of salsa and |
|
|
57:22 | , these ridges and imaginations and the common species of what these gyra provide |
|
|
57:31 | is the surface area. And the in the three dimensional wiring and connectivity |
|
|
57:39 | these neurons wiring is connectivity because it's wiring cables. So if you have |
|
|
57:45 | a, a flat box, you put the cables through a flat |
|
|
57:48 | That's, that's all you have. , if you shape that box in |
|
|
57:53 | ridges and edges and curves and stuff that, now you introduce a lot |
|
|
57:58 | complexity into the system. So uh , you see stimulus structures, but |
|
|
58:07 | you see that some animals like rats, dolphins even will have very |
|
|
58:13 | factor balls which are actually very small humans and certain structures are bigger than |
|
|
58:20 | depending on the function that they need perform or what they need to do |
|
|
58:25 | order to survive and procreate in their environments. Whenever we talk about |
|
|
58:32 | we have to remind ourselves of some medical terminology. Interior rostral, |
|
|
58:40 | coal dorsal, the back, the , the front, medial in the |
|
|
58:49 | , lateral away from me. So more lateral you are the more further |
|
|
58:55 | you are from midline. When we the brain, we typically cut it |
|
|
59:02 | slices because we want to reveal the anatomy and connectivity of the brain. |
|
|
59:07 | typically this is done as miso horizontal sections or coronal sections. Uh |
|
|
59:17 | this is for example, a, miso view off the inside of the |
|
|
59:22 | , the two left and right hemispheres right through the mid line here and |
|
|
59:29 | major parts, you know the the left and reb hemisphere there is |
|
|
59:34 | uh uh of course different functions that performed by left and right. We |
|
|
59:40 | the language areas, for example, the left atmosphere, cerebrum are bellum |
|
|
59:46 | stem spinal cord and will go over lot of these different areas of the |
|
|
59:52 | and their functions in the next couple lectures. So you have cerebral and |
|
|
60:00 | hemispheres where the sensory and the motor is processed in the contralateral fashion. |
|
|
60:08 | that when I move my right it's my left motor cortex and constructed |
|
|
60:15 | move my right arm. Cerebellum or little brain in the back of the |
|
|
60:23 | the cerebral cerebellum is also involved in control. But cerebellum controls the movement |
|
|
60:33 | the same or if the lateral So left cerebellum will control left or |
|
|
60:39 | cerebellum will control right uh motor uh and movements is the area where we |
|
|
60:49 | a lot of cerebral cereal and So, in anatomy, besides the |
|
|
61:04 | lateral interior, posterior superior inferior, , we should probably add on to |
|
|
61:10 | diagram too. You also have these names. The typically the first is |
|
|
61:19 | origin where it is coming from. if it's cerebra cerebella, that means |
|
|
61:26 | are inputs coming from cerebral into And if it's from cerebellum to |
|
|
61:36 | that's cerebella, cerebral. So we'll study tracts, for example, |
|
|
61:41 | the spinal cord spinothalamic, that means from the spine to the thalamus, |
|
|
61:48 | means it's from the cortex into Ok. Brain stem is the area |
|
|
61:56 | has uh nuclei that regulate a lot vital body functions, breathing consciousness, |
|
|
62:06 | of body temperature. For example, , heart beat, it's very important |
|
|
62:14 | these vital bodily functions. Not as for the cognitive functions. Of |
|
|
62:21 | in the periphery, we have peripheral system and we have the somatic which |
|
|
62:28 | voluntary. So we talked about joints, movement of the muscles, |
|
|
62:34 | sensory and motor. We looked at reflex arch which illustrated both, although |
|
|
62:43 | didn't talk about the sensory inputs and nerve endings that will carry the |
|
|
62:47 | We look at that when we study soma sensory system, but all of |
|
|
62:53 | sensations from basically your head down below brains, stone somatic sensory sensations and |
|
|
63:07 | the motor output, my motor command move my right hand will come from |
|
|
63:13 | left motor cortex and basal ganglia and move my right hand. Ok. |
|
|
63:22 | this is, this is, this voluntary. Uh and visceral is autonomic |
|
|
63:32 | something that you don't really control. uh internal organs, blood vessels and |
|
|
63:41 | . And there is even a mesenteric system that surrounds our gut, surrounds |
|
|
63:51 | digestive system. And it is emerging as complex as the C N |
|
|
63:58 | And there is a lot of interactions the last decade and studies that are |
|
|
64:03 | what is called the gut brain axis how the microbiome in your gut because |
|
|
64:11 | carry a lot of microorganisms and bacteria probiotics and things like that in our |
|
|
64:16 | , how their presence, the genetic metabolizes that they produce in our digestive |
|
|
64:25 | and helping us digest. And sometimes setting our digestive system, how all |
|
|
64:29 | these things are intricately interacting and can intertwined with the, with the, |
|
|
64:35 | the brain function. Oh, so everything from neck down when we're talking |
|
|
64:44 | per nervous system, everything from neck in the spinal cord is motor nerves |
|
|
64:51 | sensory inputs coming in. Everything from up is a part of the central |
|
|
64:57 | system. It's the brain stem. . And that processes the information from |
|
|
65:05 | head and the face and we'll talk that. In the next lecture, |
|
|
65:09 | learn about the cranial nerves too. brain is also protected apart from being |
|
|
65:15 | by a really thick skull. It has these meninges that protect the brain |
|
|
65:25 | times the dual matter or the hard . So dually, you have Arachnoid |
|
|
65:32 | or arachnoid membranes. And on the surface of the brain tissue, you |
|
|
65:37 | the PM MO the jungle model that the nutrients and support and uh protection |
|
|
65:46 | the brain. You can see there's lot of microvascular, your blood vessels |
|
|
65:51 | innervate into the brain. And throughout brain, the smallest distances between the |
|
|
65:58 | is only 50 micrometers inside the So there's a a lot of |
|
|
66:03 | innovating in, in the brain dura is uh hard. A mother. |
|
|
66:10 | is literally hard. It is something cannot poke with a finger. You |
|
|
66:17 | to cut through it and you have typically use a, an experimental |
|
|
66:22 | a scalpel or a very sharp knife cut through dura matter. So it |
|
|
66:28 | is like a very thick durable skin that is sitting right underneath the |
|
|
66:35 | protecting the brain. Well, we about great trepidations. Remember we |
|
|
66:41 | well, uh at first, it believed that the trepidations maybe were a |
|
|
66:47 | of torture. And then it was that maybe they were actually medical procedures |
|
|
66:54 | they were necessary for the conditions that you to actually open the skull and |
|
|
67:02 | potentially a window into the brain. now imagine a situation where you have |
|
|
67:09 | injury or you have an aneurysm which abnormal blood vessel, uh thinning of |
|
|
67:18 | blood vessel wall, the blood vessel , you have a stroke. What |
|
|
67:24 | to the blood, the blood will in this area depending on the size |
|
|
67:28 | the breakage and the leakage, the . What does next? It starts |
|
|
67:36 | . The clog is hard, it causing pressure, it starts causing pain |
|
|
67:41 | the wound. The only way this can be cleaned up is if you |
|
|
67:46 | the skull, open the window into brain like in brain and clean it |
|
|
67:53 | . And if it is happening in locations. You would have to do |
|
|
67:57 | brain rens. If there is a build up abnormal fluid, build up |
|
|
68:02 | Cebr spinal fluid, you may have repeat that procedure multiple times and that's |
|
|
68:08 | we saw evidence also of multiple uh in the same location, not in |
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68:14 | locations but repeated multiple times. Kind . Let's see where we are, |
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68:20 | out of time. So we'll leave here today. When we come |
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68:23 | we're gonna continue talking about the central system and stand by for more information |
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68:30 | your |
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