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00:04 | Welcome to Neuroscience Lecture three. It's first lecture of us discussing some of |
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00:10 | basic features of neurons and glia neurons numbers comprise about 10% of the total |
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00:21 | of the brain cells. So glial are a lot more popular. There |
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00:27 | much greater number of real south in brain than there are neurons. |
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00:34 | despite this 10 and 90% if you at the scientific literature on neuroscience, |
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00:44 | self communication on the brain circuits, will soon see that most of the |
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00:50 | is being done on neurons And it's the reverse, 90% of the work |
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00:56 | done on 10% of the neurons and of the work was done glia and |
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01:01 | was historically the case for many years we discovered glia and neurons. And |
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01:09 | is because glia which disciples into glue thought to serve a supportive role sort |
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01:19 | like supportive cells, maybe maintenance cells the brain and we perceive neurons and |
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01:29 | connections and neuronal circuits. The place the action took place the most important |
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01:35 | for neural transmission for electrochemical communications, plasticity and so on. In |
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01:44 | neurons in the brain are like chocolate in the chocolate chip cookie and you |
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01:55 | have a cookie really. Chocolate chip without miglia without the dough. But |
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02:03 | cookie is not going to be interesting having the chocolate chips in it or |
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02:08 | . Peanut butter cups, whatever is preference is. And finally for us |
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02:14 | be forming misunderstanding of of neurons and as we discussed in the history historically |
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02:24 | . The gain in the brain is in the stand meaning that you need |
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02:30 | stain the brain cells to reveal their to reveal their precise anatomy. And |
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02:39 | are different stains that we've discussed. discussed the Golgi stain and we called |
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02:43 | Golgi stain stands only a fraction of , only one to few percentages of |
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02:51 | of the neurons. If you apply silver nitrate stain on the brain |
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02:56 | only a small fraction of neurons are to pick up that stain. But |
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03:01 | cells that pick up the Golgi stain reveal their precise morphology. They're |
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03:08 | Rights are axons all of their So it's very useful in describing the |
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03:15 | morphology but it will not reveal the network or all of the cells. |
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03:19 | so to reveal all of this off the network. And to build what |
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03:27 | call the site of architecture. The , architect tonic methods that dr comedian |
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03:32 | unused. There was another stand called Missile Steam. This will stand unlike |
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03:39 | stand will stay in all of the across the board and that kind of |
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03:44 | you would want to use to describe stacking the geometry of the south, |
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03:49 | density, the layering of the south the brain matter. The game and |
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03:58 | brain is mainly understand because the rain spain is mostly in the plane. |
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04:05 | a famous phrase from from chameleon So neurons and neurons really that different |
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04:17 | the rest of the cells in the . And in reality there are certain |
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04:22 | of neurons that are just like the cells in the body. You have |
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04:26 | selma, you have the nucleus, have all of the other organelles that |
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04:31 | have learned about. You have mitochondria which is a source of energy. |
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04:36 | have poly ribosomes and rough and smooth plasma critical um where you have the |
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04:45 | and translation off the pro dance and of the proteins by the golgi complex |
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04:54 | reach their final destiny whether they're membrane or cytoplasm proteins. But then there |
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05:01 | certain features of this neuron that are that you do not see in other |
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05:08 | . And in particular it's the down . And if you look even closer |
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05:13 | top of these dendritic shafts, you these protrusions and these protrusions are the |
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05:19 | spines. And we talked about how modern day neuroscience we can actually visualize |
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05:25 | spines is the site where most of connections and connectivity will take between the |
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05:30 | . So most of the inputs from neurons will contact dendrites and dendritic |
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05:36 | And the dreaded sponsors are also very elements. The most malleable elements, |
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05:41 | that you can change the shape of spines. You can eliminate these |
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05:48 | you can grow new spines and it the most plastic and easiest way for |
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05:53 | brain to respond and to strengthen connectivity also to respond to the environment and |
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05:59 | plastic. So rather than eliminating the process the whole done right. You |
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06:05 | eliminate one or 2 spines or you add a few spines. So this |
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06:11 | quite unique for neurons and it's You also have axons. Axons as |
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06:18 | mentioned, will contact mostly done dried brittle spines, but also so much |
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06:23 | the neurons and axons, their myelin So glia contribute to the myelin |
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06:29 | which is essentially insulation of the action the axons. A cell will generate |
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06:38 | action potential right here at the axon hillock. So this is also something |
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06:44 | is unique to neurons. It has at the level of the axon, |
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06:48 | segment the initial axonal segment or axon hill up is the place where the |
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06:56 | potential is going to get generated all the information that comes into dendrites and |
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07:02 | spines. Most of it or some it. It just depends whether these |
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07:10 | are excited or inhibitory these neurons and spines will be receiving both excitatory glutamate |
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07:17 | transmission excitation and also inputs from the cells that are releasing Gaba which is |
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07:25 | major inhibitory neurotransmitter. And so the as they come into the done right |
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07:31 | then don't experience and notice that there an optical down right here which is |
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07:36 | the apex of this is a typical neuron that has shown because it has |
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07:41 | pyramid like structure as the apex or peak. And this is the optical |
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07:46 | right. And then it has the and off the base you have these |
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07:51 | gun rights. So all of the coming into the dendrites and dendritic spines |
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07:56 | then essentially get processed and integrated all that information into the south soma. |
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08:04 | makes the decision. The selma makes decision. Together with axon initial |
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08:11 | this axon initial segment, whether there enough deep polarization in this entire complex |
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08:17 | to produce an action potential. And that action potential gets produced, it |
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08:23 | gets conducted down the axon and the nation that you see. Myelin sheets |
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08:29 | wrap around the accents. They act like insulation for the wires. So |
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08:35 | happens if you strip the wire from cable, electric arcing over a |
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08:42 | Exactly, electrical signal will leak And electrical signal may not reach what I'm |
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08:48 | in the computer. That's the first would be abnormal traveling of the axons |
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08:55 | leakage of the current from this Making the cells unreliable in their |
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09:01 | Okay, so organ Al's and the processes. Uh, it's very |
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09:12 | You have jeans, you have genetic , You have transcription. You have |
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09:18 | code RNA. All right. RNA a messenger RNA. And this is |
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09:27 | happening at the level of the nucleus inside the nucleus we think that there |
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09:33 | these sort of like little busses, shuttles if you may that shuttle through |
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09:39 | nuclear pores through these openings in the exporter shuttle this messenger RNA into the |
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09:48 | and inside of plaza you have So transcription, gene code translation. |
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09:58 | you're translating the messenger RNA into the . Mhm. This is your gene |
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10:05 | you know you have entrance and Exxon's there is a process of transcription creation |
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10:16 | RNA. And then there is a of splicing, mm hmm where certain |
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10:24 | are removed. And during the splicing you get this messenger RNA that now |
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10:32 | encode for a protein of interest. a receptor channel protein. This this |
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10:41 | processes. During the splicing process you have what is called splice variants. |
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10:47 | removal of the intron regions and reshuffling the entrance and axons may have a |
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10:57 | variation during the splicing process. Splice may become proteins that have slightly different |
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11:08 | to them, slightly different functions but very very similar to each other. |
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11:14 | variants is what makes us different butt variants also can cause genetic translation abnormalities |
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11:26 | in abnormal protein information causing neurological in case because we're talking about the brain |
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11:34 | abnormalities of neurological disorders too. So is normal splice variants and there's pathological |
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11:43 | pathology that can be associated with splice . But this process is very basic |
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11:50 | that you've learned in high school We're not going to be reviewing many |
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11:56 | about some of these basic things organelles as rough and the plasmid particular um |
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12:03 | have the ribosomes, you have the up in the plasma articular, you |
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12:08 | ribosomes surrounding it. You have polarized and complexes. Once this messenger RNA |
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12:16 | out, it can then be created a protein. And that protein can |
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12:24 | cytoplasmic, meaning it's a protein that destined to floating around the cytoplasm. |
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12:30 | in some instances there is newly synthesized that embed themselves in the plasma membrane |
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12:38 | their membrane associated and they may be membrane channels. They could be just |
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12:44 | on the membrane on the inside of cell. But these are basically the |
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12:49 | major pathways membrane balance and Frida side solid floating proteins. What we No |
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12:59 | and again, you'll probably hear much explanations if you're taking genetics or if |
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13:04 | taking uh cell biology, you may things as jean micro race and what |
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13:13 | jean micro race and what is jean array profiling. So we live in |
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13:19 | post genomic era, meaning that we we know that the gene code and |
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13:25 | think we know what the gene code for. And by the way, |
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13:30 | of the cells, all of the and all of the cells in the |
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13:35 | and this nucleus will contain the exact gene code as the other cells. |
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13:41 | neurons will contain the exact same gene as lee ourselves. Same gene |
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13:49 | There's a heart muscle cells but during transcription process, of course, only |
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13:55 | subset of these genes get expressed. that's how you get A variety of |
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14:01 | to 250 or more different subtypes of in the cns. It's a subset |
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14:08 | genes, potentially splice variants also that to the subtyping of different health. |
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14:16 | we know what the code is. know what the code Codes four. |
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14:21 | now we can make a synthetic code synthetic DNA. And you will see |
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14:29 | around the university. How many base you want? We can create uh |
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14:39 | a strand uh if you're liking basically they charge you, you know |
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14:47 | per megawatt based mega bass or something that. But the because we know |
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14:55 | and because we know what things go . There are these things that are |
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15:00 | micro race and they're really just just small microscopic plates And these microscopic plates |
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15:07 | contain thousands, 10, 20 30,000 wealth in them. So these little |
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15:14 | micro welds a little openings. And you do is you load up these |
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15:20 | wells with your synthetic DNA with gene sequence. So you know, 30,000 |
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15:32 | . And you know the sequences 30,000 that code that that sequence codes for |
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15:39 | in jeans. No, you lay of these. There is commercially made |
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15:45 | arrays or synthetic DNA in it. , what you can do is you |
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15:52 | have a bird's eye view or an of what are the gross changes, |
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15:58 | are some of the big changes that happening? And you can take brain |
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16:03 | and brain to and let's say that brain one is normal and bring to |
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16:10 | is a bill optic brain for So it's an abnormal brain that has |
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16:17 | neurological disorder. So you take the , one is labeled in red. |
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16:23 | take another vial from the brain. you put the brain tissue in |
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16:28 | Okay marginalized. Do the whole procedure labeled green and you mix the two |
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16:36 | apply to D. N. A right? So the gene that has |
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16:42 | expression and brain too will show up red And the gene that has reduced |
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16:51 | in brain. one will show up green genes that have equivalent expression. |
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17:01 | will show up as yellow. Okay no change. Okay so what have |
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17:07 | done now now you have analyzed and to two brains and because you have |
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17:14 | different stands the red and the you know which one is coming |
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17:17 | which brain? Now that molecule of that is in the brain is applied |
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17:26 | this solution is applied into the into these micro wells. And these |
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17:33 | have a synthetic strand of DNA with specific sequence look at it as a |
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17:39 | complex velcro piece of velcro and that piece of velcro needs to match an |
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17:45 | piece of velcro to precisely fit into . If it does, then it |
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17:50 | harbor more and more and more and show that there's more of that gene |
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17:54 | less of that gene express. So is a really good technique. Now |
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17:59 | compared brain one on brain too to a bird's eye view of the changes |
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18:04 | the whole brain wind the whole brain you have homogenized brain tissue, unless |
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18:12 | gonna take one structure from the brand , you're gonna compare once they're a |
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18:16 | , healthy cerebellum too and neurologically impaired epileptics are available but you'll still just |
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18:23 | about cerebellum. So you will not about specific cells necessarily, but you'll |
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18:27 | about the genes. And now when get a result from the micro |
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18:33 | you will get hypothetically 200 genes going 500 genes going down the expression then |
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18:45 | going to say, well, That's great. But that's a |
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18:51 | And I cannot even do my PhD one gene, there's 201 up 501 |
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18:58 | . What do you do that You say? Okay, well in |
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19:01 | , we know That out of 300 up 500 down and epilepsy, |
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19:07 | know that these 50 genes are extremely for epilepsy because we're looking at epileptic |
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19:14 | And we know that from other studies there's models, there's genetic models of |
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19:19 | . So 50, okay, that's . Right? And from these |
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19:25 | 25 went up 25 went down, see what is what is important. |
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19:33 | you're gonna say, well, which went up the most? So out |
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19:37 | this 25 at one top you'll Oh look at these, The 11 |
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19:42 | two actually is 200 times the normal And the others are maybe just 20 |
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19:50 | of the normal expression. So you say, well maybe it's this because |
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19:55 | like so prominently over express this And then you look at the other |
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20:01 | that's under express and you say maybe those bottom ones that are the lowest |
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20:05 | expression levels are the most important. you may be right, but there |
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20:10 | a sequence also in jeans and there's sequence in what the genetic expression and |
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20:18 | ends up in the interaction of the downstream. So then your boss will |
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20:24 | , I'm interested in these five genes you have to do your PhD on |
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20:29 | too. And so then you're gonna and do about half a year of |
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20:35 | and literature analysis and stuff until you're end up picking two out of those |
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20:39 | genes and pursuing their further studies. micro rates are very useful to give |
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20:47 | complete bird's eye view of the major . But when I say that you |
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20:54 | say that the thing that changed the is the most important thing because there |
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20:59 | be a precursor gene that leads a change that leads to this big |
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21:04 | And the sequence of advances small change precursor change is actually more important than |
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21:09 | this very large change in another Smooth. And the plasmid reticulated is |
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21:18 | you have put in folding and calcium . You also have internal calcium |
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21:26 | And in neurons you heard another south . And calcium regulation is important in |
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21:32 | . Calcium is not only a Evelyn catty um It's also a secondary |
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21:38 | . And the neurons you will not free to set a solid calcium floating |
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21:43 | in high concentrations. Most of it bound up and most of it is |
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21:49 | bound up. And if you have side of solid calcium it can act |
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21:54 | both the physiology changes in the number potential levels as well as as a |
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22:01 | messenger in the intracellular cascades. And very tight regulation of calcium inside |
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22:06 | Special inside neurons Golgi apparatus is where have post translational processing and protein sorting |
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22:13 | determine their final destinations. You learned crab cycle in high school and so |
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22:24 | I. And then I learned Krebs in college and so will you. |
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22:32 | then I learned crop cycle in graduate and every time I learned Krebs cycle |
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22:39 | was learning it like renew. Again it's pretty complex actually. And then |
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22:47 | not going to talk about the home chains and all of these things. |
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22:54 | you should know that most important thing this organ al's that our mitochondria the |
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23:01 | of energy in the body and the they produce the denizen triphosphate which is |
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23:06 | peace. Denison is not only a of the denizen triphosphate for A. |
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23:15 | . P. Dennison. Di a dennison is also a neurotransmitter neuro |
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23:20 | in the brain. And so we understand the denison function. So denison |
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23:24 | the brain is what makes you So eight ep gives you energy and |
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23:29 | you. But if you take a core molecule of ADP a dentist in |
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23:33 | dennison by itself makes you sleepy and which most of us had this morning |
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23:41 | the form of coffee chai, tea or whatever else. Caffeine also acts |
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23:49 | the dentist and receptors. So you this mechanism today is just a teepee |
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23:55 | source of energy. You have this interesting structure. The outer and the |
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24:00 | membrane of the mitochondria. Um With imaginations that are called Christie and you |
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24:07 | have dietary and stored energy sources. the more active neurons are, as |
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24:13 | was telling you about the brain maps those hotspots that you can visualize in |
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24:17 | brain, the more active, the are, the more energy and oxygen |
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24:23 | going to draw to themselves. The protein, sugar and fat they will |
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24:30 | glucose and they will through conversion peru acid and oxidation will produce ATP And |
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24:39 | . 0. 2 and the brain a system that is driven outside of |
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24:48 | normal equilibrium because brain brain waves only 3 1/2 or so. And it |
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25:02 | only a couple of percentages of your body mass depending on on the on |
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25:09 | body mass. Remember we're not for , so we're not going to call |
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25:14 | , small, small headed people as and big headed people as geniuses. |
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25:21 | ? So so we have this arrangement it's just a fraction a few percentages |
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25:27 | the total body mass And the brain 20 of the total body energy. |
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25:38 | why it's a system that 3% doesn't for 3%. is asking for 20% |
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25:44 | total body energy. So 20% of you're eating, breathing, drinking, |
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25:56 | synthesizing, metabolizing in the body. goes through the air conditioner of the |
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26:07 | very high, very high energy and very high metabolic demand. In other |
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26:14 | , neurons require a lot of A lot of energy to be active |
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26:19 | your brains are not in active when sleep either. You're consuming a lot |
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26:25 | energy during sleep. Your body is moving well. In some cases you |
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26:31 | moving and maybe even talking but it's to a certain phase of the sleep |
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26:38 | . And in general, what you to think about is this membrane that |
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26:45 | neurons is very fluid ISSE. And this goes to the concept of plasticity |
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26:52 | the ability for the selves to rearrange structurally and also functionally there's this dynamic |
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27:01 | mosaic model of the plasma membrane which a phosphor olympic bi layer. You |
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27:08 | the polar hydro cilic ahead and then have the hydrophobic fatty acid chains that |
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27:21 | on the inside of the membrane. it's a fossil lipid bi layer. |
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27:26 | have carbohydrates, you have fat cholesterol in their foster lipids, lipoproteins. |
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27:33 | have trans membrane proteins. Some of trans membrane proteins are channels which means |
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27:39 | will allow for the passage of And that's how fast signaling across plasma |
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27:44 | in neurons happen. And other there proteins that are not channels. So |
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27:50 | may be g protein coupled receptors that downstream through the signaling cascades, cellular |
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27:58 | holding this phosphor lipid bi layer is of skeletal elements and these side of |
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28:07 | elements can rearrange themselves. So, the side of skeletal elements become |
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28:14 | they depolymerization or they become longer problem chains because a slightly different structure and |
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28:23 | different fluidity around the surrounding membranes. , I'd like to show this very |
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28:31 | video of a fluid mosaic model. discusses just that improving the living machinery |
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28:45 | the inner cell and the harsh conditions the outside world stands themselves. Plasma |
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28:52 | as crucial as this barrier is. surprisingly flexible. What's your name |
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29:05 | Remember actually assembled into a double play their tails with no water is there |
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29:12 | attractive the ones on cholesterol and a trouble. And you have the basic |
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29:19 | of the. Mm hmm. We find giving programs various questions for |
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29:29 | For instance, they received signals from world outside where they transporting nutrients in |
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29:37 | . So nature composes the membrane and molecules are last dictionary. They constantly |
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29:51 | infrastructure, position. The survival of life rests on this veil of interior |
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30:07 | . So the molecules the membrane this is and the molecules even trans membrane |
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30:13 | that are embedded in they move through membrane, they constantly change their |
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30:20 | And in neurons this movement can be fast in neurons, proteins can move |
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30:25 | meters in milliseconds, micrometers and Remember that the diameter of the selma |
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30:33 | the neuron is 10 micrometers. So talking about proteins that are entering into |
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30:41 | parts of the number rains and this is influenced by external activity. So |
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30:47 | is a certain type of you can steady state amount of this fluid this |
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30:53 | and then once you have heightened levels activity, there is a lot more |
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30:57 | going on with these protests across plasma and the site of skeletal elements that |
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31:03 | underneath are also moving. And that's you can change the shape of it |
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31:08 | didn't spine because you can change the studs that are holding up the house |
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31:16 | the floor and the ceiling of the that dendritic spine. and the studs |
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31:22 | be like the side of skeletal So you can do a rearrangement in |
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31:26 | house, you can remodel the house make a third bedroom and you do |
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31:31 | by you know adding a stud and some drywall in it. And so |
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31:36 | is what the dendritic spines do. rearrange themselves structurally the survival of all |
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31:47 | rests on this veil of material Just to acknowledge that between the living |
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32:12 | . So the fluid mosaic model and the sight of skeletal elements, you |
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32:16 | three types of micro two bills, elements and micro filaments. You have |
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32:24 | micro two bills that are comprised of turbulent molecules and there are about 20 |
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32:29 | in diameter neuro filaments are about 10 in diameter. And the smallest elements |
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32:36 | the micro filaments that are comprised of active molecules. So the more of |
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32:40 | active molecules to aggregate the prelim arise chains. And you can also depolymerization |
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32:46 | break them up into smaller chains. is a cross session section through the |
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32:54 | . And what you see is first all this this area here that looks |
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32:58 | of like a channel. If you you're used to looking at the sonar |
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33:03 | from depth finders, it looks sort like a channel and then these are |
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33:08 | edges of the channel and these edges the channel. You can see these |
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33:12 | lines and these are myelin sheets. is my elimination that is found around |
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33:18 | but inside the axons you see these like strings like over here it looks |
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33:26 | sort of a spaghetti running across These are micro tubules and these are |
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33:34 | we refer micro tubular highways. So a lot of transport, active transport |
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33:44 | proteins, peptides, things like that happened along the micro tubules. So |
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33:50 | that get made in the soma or that are in the periphery and need |
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33:56 | be recycled back to the soma. travel along these micro tubules and so |
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34:03 | have parallel pathways for these micro tubular that that carries the information and the |
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34:11 | of these active molecules to become shorter longer. You can think of it |
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34:17 | the side of skeletal elements causes the of the plasma membrane that they're |
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34:22 | So if you rearrange the structure you're also going to change the shape |
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34:27 | the dumb driver dendritic spine and if change the shape, you're going to |
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34:31 | the levels of its activity. Also structure and function are intertwined, |
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34:41 | This is an example of a stained stain which is tubular lint, the |
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34:49 | state which is active and in purple have the nucleus and this is a |
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34:56 | cell. It's just as an example using the spider blast self and it |
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35:04 | you something, it tells you that larger elements, the largest side of |
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35:10 | elements are located around the nucleus. is really supporting and protecting that structure |
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35:18 | the nucleus. But the smallest the active molecules that comprise micro filaments |
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35:29 | and you can see that there's arrangement all three of these side of skeletal |
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35:34 | . So they're intertwined. But on micro scale, you see that the |
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35:39 | molecules in blue are located at the edges on the outskirts of this |
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35:48 | I envision each neuron or each cell a city. It has its |
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35:53 | it has highways going in and has of communicating. And it has these |
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35:59 | boundaries or in old medieval cities, walls and in neurons. These walls |
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36:07 | plastic. And so you can see these small elements that are in the |
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36:13 | periphery closest to the plasma membrane. changes in the structure underneath would then |
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36:19 | the shape, overall change in the and the surface area of the plasma |
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36:32 | . I thought I changed the slide it keeps popping up again. I |
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36:37 | am not a fan of the So, let me today, we're |
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36:45 | to introduce our first neurological disorder and introducing it here because it kind of |
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36:53 | sense with certain aspects of some morphology anatomy that we're studying. What I |
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37:02 | for everyone in this class to do to make a page in your |
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37:11 | maybe at the end in the middle your notebook, a neurological disorders and |
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37:18 | make a page and dedicate one page Alzheimer's disease. And then when we |
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37:24 | about multiple sclerosis, dedicate another page multiple sclerosis. And when we talk |
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37:30 | epilepsy, dedicate another page to So when we talk about autism spectrum |
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37:39 | , Dedruction Page, two authors expected . You will be learning terminology and |
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37:44 | little bit of that terminology will be terminology to in understanding these neurological |
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37:54 | And uh, what you're seeing here a slide on Alzheimer's disease. The |
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38:05 | hallmarks of Alzheimer's disease. Remember what said, neuropathologist study neuropathologist study changes |
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38:14 | brain tissue abnormalities of normal stains and on. And brain tissue. |
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38:22 | what you're looking here on the left a normal brain, normal neurons and |
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38:30 | the right, you know, looking mm hmm. Great on the |
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38:38 | you're looking at the brain both in image is a B and C. |
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38:43 | the right. You are looking at brain that has severe Alzheimer's pathology. |
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38:51 | , there's certain things that we may to know and understand when we talk |
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38:57 | neurological disorders is Alzheimer's disease and developmental . There's Alzheimer's disease, a normal |
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39:06 | of aging. When do you think disease is more prevalent than twenties |
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39:14 | fifties, sixties seventies eighties, the you are, the more likely you |
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39:22 | to develop Alzheimer's disease, it's a , it's not a normal part of |
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39:27 | . So when you talk about first of all, what is the |
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39:33 | that you're talking about? Alzheimer's is is a form of dementia. So |
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39:43 | is how you define Alzheimer's is a of dementia. Then you will |
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39:49 | okay, so what do people experience they have Alzheimer's disease? And when |
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39:56 | talk about what people experience, you about, what is it you talk |
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40:03 | pain? Is it pain, loss memory, confusion, anxiety, |
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40:13 | disorientation. What are these things? mechanisms of action these symptoms? Somebody's |
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40:24 | things. You're observing it as a and then you're forgetting things every |
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40:29 | Say something is wrong. I'm trying to forget what I'm forgetting. Then |
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40:35 | a symptom. Mhm. So once patient has that symptom, what is |
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40:45 | on in the brain, what is pathology? What is the mechanism behind |
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40:52 | disease? Alzheimer's disease? You have hallmarks. Pathological hallmarks. There is |
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41:02 | formation of amyloid plaques that are also to as beta amyloid plaques. |
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41:11 | I'm glad you guys are taking notes they typically will have to to a |
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41:16 | questions on neurological disorders in each And I may ask you is amyloid |
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41:26 | , the neural liberally tangles. They're of the Alzheimer's disease pathology. And |
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41:31 | ask you abnormal dendritic spine density? that a part of the Alzheimer's disease |
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41:39 | ? Is it one of the Well, so you'll have to know |
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41:43 | information. So we're getting to? won't be studying this today in great |
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41:55 | and as far as the abnormal protein and how it's happening and such? |
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42:00 | also the reason why I want you leave a page is we'll be coming |
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42:04 | to Alzheimer's disease. For example, we talk about neural transmission and we |
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42:09 | about acetylcholine, we will talk about pathology and loss of the colon ergic |
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42:16 | , but we will not do it . We're going to have a gross |
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42:19 | understanding of Alzheimer's disease is. But a few lectures later, you can |
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42:24 | back to that same page on Alzheimer's and add more information on the chemical |
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42:30 | and that specific subtypes of cells that involved when data, amyloid plaques |
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42:36 | They referred to as senile plaques they to as calcification, plaque. Sometimes |
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42:43 | abnormal aggregation and calcification of proteins on outside of the south. This is |
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42:49 | hallmark. The second hallmark is intracellular this is the formation of neuro february |
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42:57 | tangles and there's proteins that are We want to discuss them. But |
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43:01 | a towel pro dam that causes the tangling of neurofibromatosis. So what happens |
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43:11 | you tangle up the side of skeletal . I just told you about external |
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43:17 | , how the goods and information gets in the same within the same |
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43:22 | So what happens if you cannot deliver or food to one part of the |
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43:30 | , those people will not survive. that damn drive will not survive and |
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43:35 | may not survive because the tangles. you've taken up and these highways that |
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43:40 | have with the lights that people follow traffic and take the turns all of |
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43:44 | sudden they're all on top of each and intertwined and inter tangle. So |
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43:49 | of all you have an ability to things and to have inside the cell |
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43:58 | , entrust cellular communication that gets 2nd of all this amyloid plaques on |
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44:06 | outside, they start physically physically causing in the tissue. So it's not |
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44:13 | that they formed and they're sitting they become like little balls of inflammation |
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44:20 | they start growing and aggregating more proteins debris and then they start affecting axon |
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44:28 | segments in particular. So what happens the amyloid plaques is they physically start |
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44:35 | parts of the Acts on initial segments now the cells cannot produce action potentials |
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44:41 | . So you have two problems on inside of the national february tangles will |
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44:48 | an ability for intracellular delivery of intracellular communication. But if you cannot |
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44:56 | things to the distal parts of the , you also cannot receive things |
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45:02 | And on the outside these amyloid plaques start damaging axon and remember that axon |
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45:09 | that axon initial segment, it turns that that accident initial segment is extremely |
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45:16 | to the extra cellular plaques And it's sensitive that only 10% reduction in its |
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45:24 | Can cause upwards of 30% failures and potential generation. So to answer your |
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45:32 | , the mechanisms are complex but mostly the cell. It has to do |
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45:37 | intracellular communication, nutrient supplies inside the and outside of the cell. It |
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45:43 | to do a lot with the synoptic and the production of the action |
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45:50 | And if you look on the gross scale, which is our image here |
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45:56 | the right severe Alzheimer's pathology is causing neuro degeneration. So you will hear |
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46:08 | disorders. That means that there is and loss of neurons and loss of |
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46:16 | tissue. And you can see massive on a gross scale in Alzheimer's |
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46:24 | there's a massive reduction, okay, shrinkage off the gray matter but the |
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46:32 | brain is completely different shape. Now you go to a doctor and you |
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46:42 | advanced state of Alzheimer's disease, can tell you that you have plaques in |
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46:47 | brain? Can the image that we're there? We're getting very close to |
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46:52 | to image the plaques in the brain invasively in the clinics. But that |
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46:59 | already a very advanced stages of the . In reality. The ultimate diagnosis |
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47:06 | Alzheimer's disease can come postmortem postmortem after when you can actually look at the |
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47:15 | tissue and say now we confirm definitively plaques, tangles, neural degeneration shrinkage |
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47:23 | the brain before that whatever you're doing symptomology is a neurologist or the patient |
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47:30 | with neuro imaging it's it's still quite for the definitive diagnosis. And so |
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47:39 | is a progression of the disease progression the disease and the symptomology does it |
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47:44 | happen if the person just wakes up they're completely confused and remember anything. |
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47:49 | usually is a gradual onset and development these symptoms. Now when you start |
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47:55 | your grandmother is forgetting your name once month and then the grandmother is forgetting |
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48:01 | name and confusing you with another person time you see her something is going |
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48:07 | . And so they're very interesting studies older people that are keeping themselves mentally |
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48:15 | that are keeping the speech areas and writing active. There's some very interesting |
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48:21 | of nuns that seem to live in environments. So they don't have that |
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48:26 | of the stimulus, you know, to be plastic to all of these |
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48:31 | by the outside world. But they reading and writing extensively and they have |
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48:37 | , very low incidences of of So this disease progresses and it may |
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48:45 | in some instances as early as 50's it can progress and when the brain |
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48:53 | are dying and you're forgetting things. are then at the end stages of |
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49:02 | disease, the brain is no longer of taking care of the body cannot |
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49:08 | because you have to have a neural in order to swallow. So you |
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49:12 | feed and at some point there's no , you know, mechanisms that get |
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49:17 | . So we will come back and more about Alzheimer's disease in this |
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49:23 | This is not the last time we about this and I know you will |
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49:27 | questions throughout. Go ahead. Is how it kills a person? Because |
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49:33 | you're not able to. Yes, it's first the conscious cognitive memory and |
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49:42 | it's some of the basic body functions the plaques, the infiltrate throughout the |
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49:50 | brain tissue. And they can start the hippocampus of the cortex and then |
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49:55 | migrate throughout the brain and spread and of a multiply and you can find |
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50:01 | everywhere. And if it starts affecting inflaming some of the brainstem regions that |
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50:08 | responsible for vital body functions and You those two. No thanks. |
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50:16 | Okay. I think this is the window. Mm hmm. This is |
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50:27 | dendrites and dendritic spines. And this the axons and all of this has |
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50:32 | have precise anatomy. The dendrites and . Axon initial hilo. It should |
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50:37 | action potential in normal functioning brains. there's a some terminology here. So |
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50:46 | hillock here we are. Action potential produced. Axon collaterals actions don't have |
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50:53 | terminal synapse actually can send off branches terminate on many different neurons. Accident |
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51:03 | button. Or if you french inquired . Ah They're referred to as Bhutan's |
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51:10 | present. Or buttons and passing axons leave these little connections and buttons as |
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51:18 | travel through until the regional terminal side connectivity. The area between the axon |
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51:27 | the dendrite or the selma is a inside synopsis and then side next channel |
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51:36 | . You see a lot of So there is a lot of energy |
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51:43 | that are necessary for the vesicles These are the vesicles that stored |
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51:50 | The neurotransmitter vesicles will fuse with the membrane and release neurotransmitter content into the |
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51:58 | cleft. That space is about 20 apart. Okay physically Chemicals will travel |
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52:09 | the space. 20 nm and the synaptic side you have receptors that we |
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52:16 | to earlier as PTSD post synaptic That means there are collections of receptors |
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52:22 | are densely located and are juxtaposed directly from the input from the axle |
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52:32 | So we'll know a lot about synaptic . Will know a lot about different |
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52:37 | . Not just glutamate and gaba but and dennison, norepinephrine and all of |
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52:45 | other good stuff that we found in brain and the peripheral as well. |
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52:50 | hmm axel plasmid transport axons as I we'll use these micro tubular highways and |
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52:59 | is engines, motors such as knesset opposite direction. That's dynamic connection will |
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53:07 | and terror gravely from selma into the . Then we'll carry vesicles will carry |
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53:14 | will carry some of the other things of pass it along along the |
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53:20 | And so there's your answer to what if you tangle up these highways. |
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53:25 | of a sudden this transport is hugely retrograde direction. You'll have a different |
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53:32 | that carries his dining, You have of plas Mick transport. And in |
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53:38 | early historical days, we used to up an axon, inject the |
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53:43 | tie up one end of the accident see how long that diet takes to |
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53:47 | through the axon in the lab. , those were the early experiments with |
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53:52 | dies. So 1 to 10 a , 10 millimeters is one centimeter one |
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54:00 | is two point five cm. Something that. And then you have fast |
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54:07 | of plans and transport like you could that using radioactively labeled nucleic acid |
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54:15 | And there's 10. The day fast millimeters. Ramirez is a centimeter 100 |
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54:29 | 10 cm. 1000 is one So that is fast Now. What |
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54:35 | you are Dwight howard? Mm Who is now the center of |
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54:46 | I know, I don't know Who is on that team actually. |
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54:52 | the point being is that there's some long axons. There's some very long |
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54:57 | men and women that have long axons the transport, you know, we |
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55:01 | it fast. But it takes a to travel and meet her in some |
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55:07 | . So this transport is important and transport is nutrients and vesicles and things |
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55:12 | happening in addition to the fast electrical that are traveling down through the |
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55:19 | Mhm. And we have these We can use tracers, retrograde transport |
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55:29 | particular. Retrograde means it's going to transported from the periphery or from the |
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55:35 | endings into the selma's. So you a question which part of the |
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55:41 | Like what neurons are connected to this of the scandal? Let's say it |
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55:46 | be another network of cells. But just use the skin an example. |
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55:49 | you take a horse riders peroxide is one of the dyes that will travel |
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55:54 | lit and the dye will get taken by the nerve endings here in the |
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56:00 | . So you injected the dye here then you'll say oh it's this network |
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56:04 | H. R. P labeled neurons is communicating or taking the information from |
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56:09 | patch of skin. Alright, there's nerve endings that from here go into |
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56:15 | neurons. It's really nice way to advantage of the interrogator and retrograde transport |
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56:21 | label things to label the projections across brain. We also have herpes virus |
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56:28 | can use retrograde transport to enter into soma rabies virus. Mhm. We'll |
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56:39 | about Herpes Zoster virus when we talk shingles, Herpes, Zoster has the |
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56:44 | to travel both answer greatly and retrograde . So some viruses have the ability |
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56:52 | do that too. But why do care about this? Because we want |
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56:56 | know the connectivity of the brain. we want to know where are all |
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57:01 | these connections between neurons. And we to know retrograde and interrogate fashion. |
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57:06 | want to use all of the virus too because you can tag viruses with |
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57:11 | label and you can see how that will travel through the cell and that |
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57:15 | light up this cell as it travels let's say a fluorescent lee label the |
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57:21 | virus and dendrites and dendritic spines. elements that if you change the site |
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57:29 | skeletal arrangement underneath the plasma numb plasma membrane is fluid as it's going |
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57:34 | rearrange itself. Mhm. These spine , first of all, you have |
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57:43 | lot more spines and synapses when you born and when you end up in |
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57:47 | adult years. So there's a lot dendritic dendritic synaptic and spine pruning clipping |
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57:54 | going on during the refinement of these into the adult brain. These spines |
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58:00 | also contain synaptic polar ribosome complexes and loaded with eight p. Why would |
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58:08 | have polar ribosome complexes in dendritic Because that makes them critics find biochemical |
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58:17 | from the soma and it's located very far away from the summer. So |
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58:21 | it needs to do something locally translates locally, it can do it at |
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58:27 | level of the dendritic spine independently. has a certain level of independence, |
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58:33 | some decision some translations from the settlement these spines come in different shapes and |
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58:42 | . They have to have precise density along the dendrites and this process is |
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58:49 | and environment dependent process. You can the spines. You can grow new |
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58:55 | . You're now taking notes, You're some dendritic spines. You may be |
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59:00 | new dendritic spines. You're going to the information. You're going to strengthen |
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59:04 | dendritic spines. You're gonna repeat it times. You'll never forget it. |
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59:08 | dendritic spine. They stay there for , many years. Mm hmm. |
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59:13 | this is activity dependent environment dependent You you start doing different tasks. |
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59:20 | start changing the spines in different parts the brain in a different way. |
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59:25 | using different dynamics. So arrangement of spines and densities of dendritic spines are |
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59:34 | important. We're actually going to end lecture today because when we come back |
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59:45 | thursday and please remember on thursday I only be in zoom. You're welcome |
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59:50 | come to class. I just will this rule for the first two |
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59:54 | Welcome to come to pass to watch video on zoom. Um When we |
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59:59 | back we will talk about mental retardation autism spectrum disorders. And so we |
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60:06 | about six minutes today and I don't to rush through it. It's a |
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60:12 | important topic and it's in a completely age spectrum from Alzheimer's disease and it's |
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60:23 | to dendritic spines and dendritic spine densities dendritic spine formation and normal synaptic formation |
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60:29 | plasticity and developing brains. Okay, why? It is important that we |
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60:35 | more than five minutes On it is currently about one in 40 boys are |
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60:46 | diagnosed with what we call autism spectrum or asd, autism spectrum disorders, |
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60:54 | is a broader umbrella for developmental and representations and different syndromes that fall under |
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61:02 | umbrella. And this has been changing the last decade. From one in |
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61:11 | boys, one in 70 girls, now, one in 40 boys that |
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61:17 | being diagnosed with A. S. . And so I would be interested |
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61:23 | maybe have that discussion on thursday a bit and see if I can bring |
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61:30 | some interesting statistics and also talk about of the mechanisms and pathologies that relates |
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61:35 | dendritic spines. one in 40 in country or. Yes. Do you |
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61:43 | the prevalence is actually increasing or the ? It's a very good question. |
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61:49 | getting smarter with the diagnosis. Of . Uh maybe we're paying a lot |
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61:54 | attention to those things. But I think the world is changing and I |
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62:00 | the world is changing in my opinion , you know, a lot of |
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62:04 | autism has to do with the social ability to communicate with others and be |
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62:09 | part of the just, you a pack, so to speak. |
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62:14 | I think that is changing with I have a prediction is going to |
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62:18 | autism a lot because families have been to be together for the last two |
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62:23 | and the whole year, they stayed at home so that child that had |
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62:28 | supervision or had no stimulation. I not enough loving care from the parents |
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62:33 | could be one of the you things that lead or at least contribute |
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62:39 | progression of autism. Then those things changing just like with pets, you |
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62:44 | pets got used to having their owners . But then when the owners have |
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62:48 | go to work, the pets are anxiety and they're freaking out. It |
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62:54 | . Yes. Could it also be opposite? Because Children don't see like |
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62:58 | facial expressions or hang out with people own age. It's either that and |
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63:02 | a very interesting topic as a But I think we learned how to |
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63:06 | people's eyes much better than the last years to and recognize maybe even fake |
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63:12 | with ice. You know, people go ahead. Dendritic spines. |
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63:28 | Dendritic spines would have their own sort a separate biochemical machinery which would require |
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63:35 | mitochondria and 80 p. And which require polarized assemble complexes too. So |
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63:42 | locally without informing the major dendritic without informing the soma that dendritic spine |
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63:49 | make a decision. I can rearrange and there's other elements that you learn |
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63:54 | that can help that rearrangement too. I have a full of questions with |
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64:00 | . So does that mean the complex and come running A. M. |
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64:06 | locally for for use precisely. Yes. Great questions. Thank you |
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64:15 | much. Thank you all for being . Thank you |
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