| 00:02 | All right. So what we did time as we overview of some of |
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| 00:05 | basic things like the organ aisles that find in most of the cells And |
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| 00:10 | course you find them in neurons um as smooth and deposited ridiculous golgi apparatus |
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| 00:19 | which is the main source of energy south producing a molecule, mitochondria fossil |
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| 00:27 | by layer which were discussed as a mosaic model, meaning that various |
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| 00:32 | even the trans membrane components that are in the plasma membrane that's possible by |
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| 00:38 | have a dynamic. We're moving through fossil liquid plasma by layer to different |
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| 00:46 | of the south And supporting structure for of overall core structure as well as |
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| 00:54 | outer number and shape is given by tubules near filaments and micro filaments of |
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| 01:02 | sata skeletal elements were micro filament comprised active molecules. There is the smallest |
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| 01:08 | you will find micro filament molecules and outer edges closer to the membrane. |
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| 01:14 | will shape that outer edges in the of for example the good expensive. |
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| 01:19 | talked about in larger elements. Such stupid violent staying here and the other |
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| 01:24 | be found closer supporting the base and core structure closer to the south |
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| 01:31 | We then discussed uh hallmarks of Alzheimer's in particular. We talked about um |
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| 01:40 | cellular pathology and intracellular pathology for Cecelia . We discussed amyloid plaques, email |
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| 01:49 | of beta amyloid plaques. Uh and the inside of the south we discussed |
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| 01:56 | february tangles. We didn't really talk telepathy of this protean tile at this |
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| 02:03 | we'll come back and talk about it . The point being that the extra |
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| 02:07 | blacks will impede on the normal network and cellular processes of the nearby neurons |
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| 02:15 | glia that are located there will cause aggregations. Uh followed baptized prudence and |
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| 02:22 | will sequester glial cells which will learn today are responsible for not only cleaning |
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| 02:31 | damage and repair, but also for of the inflammatory responses uh in the |
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| 02:40 | . And so these plaques can can in size. They can migrate, |
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| 02:45 | and they can destroy the connectivity and actual potential firing cells. Tangles will |
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| 02:52 | with intracellular external transport and can also abnormal activity inside the south. And |
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| 03:00 | the gross anatomical pathology of severe advanced disease. Post martin. He was |
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| 03:06 | shrinkage of the brain shrinkage of the matter. And we've also, in |
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| 03:12 | to pathology discussed symptomology are loose symptomology some late symptomology of Alzheimer's disease. |
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| 03:21 | also discussed a little bit about but we'll conduct it when we talk |
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| 03:25 | Alzheimer's disease. Uh So these are of the important things that you start |
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| 03:32 | about associating and as I mentioned, should create a little tap for Alzheimer's |
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| 03:37 | and some other neurological disorders that will at in this course. All |
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| 03:43 | So now let's head back to the will be replaced with a slide that |
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| 03:49 | telling you about just a second And uh and we discussed accents accent |
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| 03:58 | segment, that's where an axon that's where the action potential gets produced |
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| 04:03 | when it arrives at maximal terminal the will result in the fusion of the |
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| 04:10 | transmitter vesicles release of neurotransmitters into the collapsed. And binding of those neurotransmitters |
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| 04:17 | the boston optic receptors will a local synaptic response in these post synaptic |
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| 04:21 | And it could be the excitatory neurotransmitter that will vote excited to post synaptic |
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| 04:27 | and be an inhibitory neurotransmitter like That will pass them out that we |
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| 04:32 | inhibit or will dampen activity in the . And also in addition to these |
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| 04:38 | what we call the amino acids gaba and glutamate. You have a |
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| 04:43 | of other uh neurotransmitters and it means some of the cells can co express |
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| 04:50 | release in some instances and baptize that of the south can co release. |
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| 04:55 | we'll talk about that in greater detail we talk about synaptic neural transmission. |
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| 05:01 | discussed the X deployment plasma transport to the fast knesset being responsible for interrogated |
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| 05:08 | and diamond being responsible for the retrograde . And we also highlighted how retrograde |
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| 05:16 | can be used for staining and in if you inject something in the |
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| 05:22 | it may get picked up by the axons and out of that retrograde lee |
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| 05:27 | deliver that stain. For example, riders peroxide is into the selma. |
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| 05:32 | you'll know exactly where the projections are from and to the periphery. Cos |
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| 05:37 | rabies virus will also use retrograde transport get that we need to be foreign |
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| 05:45 | to infect the cells fully and take their genetic machinery. Dendritic spines are |
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| 05:52 | important. And we talked about how the most dynamic elements, the most |
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| 05:58 | elements. This is where a lot connectivity, the south's happen and these |
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| 06:03 | expands. But they're also someone by independent units because they have followed around |
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| 06:09 | cinema complexes uh and they have pretty amounts of mitochondria in them as |
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| 06:19 | Yeah. Another disease that we've introduced time was autism spectrum disorder fragile X |
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| 06:27 | . And we said that this is example of where you now see how |
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| 06:34 | anatomy of dendritic spines is very important normal development of mental development for normal |
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| 06:41 | and connectivity in the brain. Whatever ends just not bill. Um Them |
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| 06:48 | on the right that has shown here a mentally retarded infant. And so |
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| 06:54 | of the infants that would have fragile syndrome which falls as we discussed this |
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| 07:00 | and spectrum disorder umbrella. They would these abnormal spine formations and that you |
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| 07:06 | see the density of sponsors affected the along the dendritic shaft is different from |
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| 07:13 | normal infant critic spine and connectivity as consequence of this plasticity is also out |
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| 07:23 | . Therefore processing emotional mental processing isn't . And we also mentioned the comorbidities |
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| 07:32 | when we talk about Alzheimer's disease, also mentioned the strong comorbidities. And |
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| 07:36 | said that in fragile X whenever comorbidities seizures from our policy. So now |
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| 07:46 | highlight how normal dendritic spine development and is so important for the brain on |
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| 07:55 | right, you see the stain on of neuron And everywhere you're seeing green |
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| 08:02 | being punked eight or the excited to with the major sectors which would be |
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| 08:08 | to eliminate synapses essentially. And everywhere seeing orange dogs and stains will be |
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| 08:15 | . Gaba receptors would be correspondent to inhibitory synopsis. And so the cells |
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| 08:22 | to go through a very fast computation order to process information from excited her |
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| 08:28 | history. To integrate all of that at the level of the selma and |
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| 08:33 | produce an action potential or not produced action potential depending on what inputs are |
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| 08:40 | into the south. So um most have four functional regions. They would |
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| 08:48 | the input region. Uh This input be coming from another neuron, from |
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| 08:53 | motor neuron, from an interneuron from neuron from half of the skin. |
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| 09:00 | example, sensory neurons reversal root ganglion into the end of the nerve foundational |
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| 09:06 | into the skin. And that information integrated at the level of the |
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| 09:12 | It is conducted through the conduct I'll which is accidents and the output happens |
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| 09:18 | the external terminals and that output can secretion in the sense that you can |
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| 09:26 | connections to neuro endocrine system to hormone hormonal release. So you actually can |
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| 09:35 | the overall para crimes sort of a levels in the body, through your |
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| 09:41 | through the neuro endocrine system. You also output on other neurons. You |
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| 09:46 | motor neurons without put onto the muscle and cause muscle self attraction. You |
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| 09:53 | have local into neurons. And we talked about different ways of classifying cells |
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| 09:58 | will come back to local engineers. can also influence that has a constriction |
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| 10:02 | dilation of the local capitalism. Micro that are found in the brain. |
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| 10:09 | classifying neurons by anatomy or morphology is popular way of doing it. You |
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| 10:17 | these unit polar cells that are characteristic invert invertebrates. They basically have branches |
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| 10:25 | serve as accents uh and receptive So it's sort of just one poll |
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| 10:33 | a way. You have one just north direction. Dendrites and |
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| 10:38 | Both process information in a way you bipolar cells and in our case we |
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| 10:45 | come back to bipolar cells when we about the anatomy of the retina. |
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| 10:51 | was a bipolar sound and that would have the north pole. In this |
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| 10:55 | it's a done dried from the south which is an accident pseudo uni polar |
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| 11:03 | because it's really not buni doesn't just one pole, It has north and |
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| 11:08 | poles. But the polls are split the peripheral axons and the central |
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| 11:15 | Sido una palla cell is a dorsal ganglion, south, dorsal root ganglion |
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| 11:21 | by the sensory cells that carry that into the spinal cord that we |
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| 11:32 | Multipolar cells comprise the majority of all the neurons. We have a motor |
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| 11:36 | here you have a criminal cell of campus and the breaking the salad, |
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| 11:41 | cerebellum with its extensive tree. You also classify neurons based on the damn |
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| 11:49 | . Some of them will have spines others will not and it's not necessarily |
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| 11:53 | it's abnormal development of not having sponsor and cells that are spying me. |
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| 11:58 | is another way of classifying them more if you look alike and I located |
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| 12:04 | to each other. Finally you can that's not finally because there's still more |
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| 12:10 | to come. Cells are classified based the connectivity. So you can have |
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| 12:16 | sells most of the production cells in brain are excited to peron. It'll |
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| 12:21 | and you can also have local into and local into neurons are typically |
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| 12:26 | Gaba releasing neurons that affect local circuit without projecting out of that circuit into |
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| 12:33 | adjacent circuits are Jason parts have been brain parts. So some of these |
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| 12:40 | can be excited or based on excitability they release glutamate, they're excitatory or |
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| 12:46 | if they release gabba. But beyond , as we know different cells in |
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| 12:51 | body as well as in the brain of types of cells will express a |
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| 12:56 | of the genetic code, which will them different from other cells and they |
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| 13:00 | express specific neurotransmitters. The neuro peptides that you can stay in for or |
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| 13:08 | self specific markers. The cells produce potentials and these very fast deviations and |
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| 13:16 | potential from about negative 65 To about , 20, positive, 40 million |
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| 13:22 | , about 100 million bowls, What happens within one or 2 seconds |
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| 13:28 | time is essentially the language by which speak to each other because you need |
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| 13:36 | produce an action potential in order to neurotransmitter and you need to release the |
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| 13:41 | in order to communicate the information to interconnected neurons. This is the first |
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| 13:48 | in Jerusalem are action to tom But Hodgkin and Huxley uh photographed the |
|
| 13:58 | at the time. There were no that you could connect now. You |
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| 14:01 | do like a lot of recordings of is done through computer control bacillus |
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| 14:09 | the computers themselves to somewhat of an to with the proper components. But |
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| 14:15 | those days this will flash on the of the silla scope and they would |
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| 14:21 | to take a picture of it and would typically be a Polaroid picture and |
|
| 14:27 | about how you would have to submit image. Then the general to publish |
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| 14:35 | . You can't scan it in and it on a USB stick or email |
|
| 14:39 | again. It's a very different So that's why it kind of looks |
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| 14:42 | taken from a silla scope and you to go to poppy Machine and make |
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| 14:49 | copies, send it to the journal the journal principle and make their own |
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| 14:52 | of this article. Yes. Uh , if the ocean like saying more |
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| 15:01 | , that's a that's a that's a question. Uh, if you can |
|
| 15:12 | on to detailed answer to that we're going to talk about things that |
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| 15:16 | called a reversal potential When we talk member and potential and we'll talk about |
|
| 15:22 | happens if the member and potentials of million balls. The cell will essentially |
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| 15:27 | hyper polarized to call it. The will be the activity in that sound |
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| 15:32 | of that cell will be dampened. it will be very hard to make |
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| 15:36 | sell react to inputs and the fire action potential. And also for the |
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| 15:42 | part It would be dominated by potassium doctrines this mindless 19. But |
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| 15:50 | the cells typically don't live that either positive 40 potential or negative 90 potential |
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| 15:58 | a long time. The member of is a random walk. You polarize |
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| 16:04 | little bit too polarized, more hyper polarized hyper polarized, More de polarize |
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| 16:09 | to polarize. The polar is Fire an action potential. So it |
|
| 16:13 | stays as a flat line actually. would use your men here, You |
|
| 16:19 | see fluctuations. So but it's a good question and we'll come back to |
|
| 16:23 | in greater detail in a couple of . So we started discussing I believe |
|
| 16:32 | started discussing this or we didn't does remember this diagram? Okay good. |
|
| 16:40 | we talked about hippocampus was restructuring the that's very well studied has three dominant |
|
| 16:47 | . Buddy, adam, raga, and orients. And what we said |
|
| 16:52 | that this circuit is a very good of different subtypes of cells that you |
|
| 16:57 | be finding in the brain. But particular in this case in the hippocampus |
|
| 17:04 | what you have is in the middle , well not in the middle but |
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| 17:09 | of in green blue turquoise colors. have the excited term projection cells and |
|
| 17:16 | excited projection cells morphological lee to look same and their projection sells because their |
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| 17:23 | and the output. The action potentials these cells will actually be projected into |
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| 17:29 | parts of the hippocampus are outside of hippocampus into the interconnected critical areas of |
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| 17:35 | brain. And so these excitatory parameter will release glutamate and the only difference |
|
| 17:41 | them is this specific self specific marker gin. Some of them are positive |
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| 17:46 | cal tendency D plus and some of are negative for contingency B minus. |
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| 17:51 | the ones that are negative for Calvin typically live a little bit outside of |
|
| 17:55 | main strike them through on the dollar the toronto cell layer which is done |
|
| 18:01 | because it is very densely populated by densely stacked parameter all south next to |
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| 18:07 | other. So the output to the regions is excited. Terry projection |
|
| 18:18 | What determines that out? But how of that excitation escapes, runs away |
|
| 18:25 | is communicated to other regions of the is entrained and controlled by the variety |
|
| 18:31 | inhibitory into neurons. This is one 21 different subtypes of inhibitory into |
|
| 18:38 | And what what's different about them is of all the location of their selma's |
|
| 18:45 | of them are located in orients Some of them are located in ready |
|
| 18:50 | layers and others are located in karama layers. So they're scattered throughout these |
|
| 18:54 | layers. The other thing is they're right? Some of them have these |
|
| 19:01 | projecting them rights and others have horizontally them. Drugs. Then these yellow |
|
| 19:08 | that you're seeing here, they represent synopsis or the inhibitor synopsis in particular |
|
| 19:14 | the inhibitory neurons will be targeting the for Karam it'll cells. And so |
|
| 19:20 | this case it would say what's the between two and 4. And this |
|
| 19:25 | a very good example and this is you have to do in order to |
|
| 19:29 | specific setback of the cell number two number four they look the sand. |
|
| 19:35 | live in the same layer from They have done rights that are projecting |
|
| 19:44 | . Their axons these yellow cops target same area around the So most of |
|
| 19:49 | parameter cells. And so the only is that # two is a basket |
|
| 19:57 | . This T. V. Which for providing and positive. It's a |
|
| 20:01 | binding protein And # four is a cell that CCK or the blue |
|
| 20:10 | Another marker positive the take home Is that the final way that you |
|
| 20:15 | discern between these cells because they both the same morphology. They're both inhibit |
|
| 20:21 | that have the same connectivity on the tourists. Also said the only way |
|
| 20:27 | this case you can discern is based their cellular markers what they produce. |
|
| 20:34 | in addition to that you also want know what activity they produce. And |
|
| 20:41 | if you look at these two cells located next to each other. This |
|
| 20:48 | on the right is actually an excited parameter will sell and this recording was |
|
| 20:53 | in my lab. It's an excited parameter cell that produces these are action |
|
| 21:00 | . It produces somewhat low frequency of action potential firing. When you stimulate |
|
| 21:05 | cell on the left next, the cell receives the same exact input |
|
| 21:13 | the cell on the right with the on the left responds with a very |
|
| 21:18 | frequency of these action potentials. So you record using differential infrared microscopy, |
|
| 21:26 | I explained to you a couple of ago is a way that you can |
|
| 21:31 | individual neurons without using the stains. once you do that and you stimulate |
|
| 21:38 | cells you immediately know that there are cells. In other words, these |
|
| 21:43 | produce different characteristic signatures of the action . If you think about these blast |
|
| 21:52 | as an input, this input, can also think of a stimulus. |
|
| 21:57 | two cells are receiving the exact same but they respond very differently. So |
|
| 22:07 | an action potential is a word, are language, Then these two cells |
|
| 22:13 | two different languages For two different It doesn't mean that they're saying the |
|
| 22:22 | thing actually is that there may be interpreting it slightly different one just like |
|
| 22:32 | would do in different languages. You a great phrase in a certain language |
|
| 22:37 | then you try to translate it into or vice versa. It just doesn't |
|
| 22:42 | or doesn't completely make sense when it translated. It's a different way of |
|
| 22:48 | something right? It could be a saying that's understood in a certain culture |
|
| 22:55 | you translate it into english and then have something about the rabbit and the |
|
| 23:00 | and then nobody understands anything but it's same thing but it's so differently. |
|
| 23:08 | now it also can be a different that gets interpreted differently. But during |
|
| 23:15 | recording you have another die which is neurobiology and Tobias items. So these |
|
| 23:21 | will have to maintain the same the same solution that you would find |
|
| 23:27 | the cell. So this intracellular recording would call it or lectured solution has |
|
| 23:33 | be mashed with the south solution. during the recording inside these elections you |
|
| 23:39 | another dinosaur, a biotin which you essentially pump into the south as you're |
|
| 23:46 | an experiment and after the experiment you take that brain slices sitting under the |
|
| 23:53 | and you can stay there for a in in Euro biotin. Just like |
|
| 23:58 | stain that we discuss Golgi stain and biden will reveal the exact precise anatomy |
|
| 24:06 | the entire neuron. The Soma is process is the accents and the gun |
|
| 24:11 | . So this is orients Latinos a larry interneuron. It has its axon |
|
| 24:18 | the article uh side of the of parameter side of parameters cell and this |
|
| 24:25 | a parameter cell that has a long that is running out and is actually |
|
| 24:30 | out of this slice into different plane it was traveling. And so if |
|
| 24:37 | wanted to publish this data and say I reported from orients like an awesome |
|
| 24:42 | local are a cell and I showed electrical recordings. I showed this infrared |
|
| 24:51 | . I even showed this what we uh reconstructions uh precise in their own |
|
| 24:59 | morphology. I would still not be to publish this information without running immuno |
|
| 25:08 | or immuno history chemistry during an additional for South pacific markets and identifying that |
|
| 25:14 | cell I'm recording for from his so statin positive and you're a biden positive |
|
| 25:21 | it is myself. And because it a matter of statin positive it is |
|
| 25:25 | one specific set by. But these different cell subtypes that we're looking |
|
| 25:33 | Okay, it turned out to be seven which is oriented Latinos and molecular |
|
| 25:40 | . So if you want to exactly which sell in the network, what |
|
| 25:46 | is speaking where it's located, how connected to other cells. And you |
|
| 25:53 | to identify precisely precisely one out of 21 subtypes in the Hippocampus then you'll |
|
| 25:59 | whoa then what's going on in the and everywhere else there's again most of |
|
| 26:05 | diversity and variety and. Ronald sometimes the brain comes from the variety and |
|
| 26:10 | of the inhibitory intern urls. Rommedahl project that information out. Mhm. |
|
| 26:21 | this is the brain circuits and If you were to take a patch |
|
| 26:26 | the cortex and use the same technique I was describing above inserting an electrode |
|
| 26:33 | the cell and stimulate that cell with same stimulus. And you would copper |
|
| 26:41 | with pepper all of these neurons during experiments from the slice, 123456789, |
|
| 26:47 | cells that you would do an experiment . And to all of these different |
|
| 26:53 | salary would present the same stimulus the input. Those 10 different cells would |
|
| 27:02 | very very differently. This cell for is called delayed stuttering because as it |
|
| 27:11 | being stimulated it doesn't immediately produce action as it is being deep polarized, |
|
| 27:16 | has a delayed response. Why is called stuttering? Because if you were |
|
| 27:21 | translate these action potentials into sound it sound like this. Uh huh. |
|
| 27:37 | is a delayed cell but once it an action potential as a dozen |
|
| 27:42 | So this is the start of the , this cell is the bursting sell |
|
| 27:57 | it accommodates which means that it has burst of action potentials in the beginning |
|
| 28:03 | high frequency but then it slows So if you were to translate it |
|
| 28:07 | sound would be this is a bursting , repeated bursting south. It has |
|
| 28:23 | same stimulus as all these other But how does this sell respond to |
|
| 28:27 | stimulus? It responds like this boosh then all of this I'm just using |
|
| 28:41 | the same language of an action This is the dialect of neurons, |
|
| 28:48 | are the dialects of your brain circuits these are specific action potential firing signatures |
|
| 28:54 | you will find in this wide diversity neurons that you find in different parts |
|
| 29:00 | the brain, in the cortex, the hippocampus. If you live in |
|
| 29:04 | the nick Doha in the cerebellum doesn't . They will all contain different number |
|
| 29:11 | different variety of different subtypes of They would speak in these different |
|
| 29:17 | Yeah. Yes being still paul. . And what I'm genetically yeah it |
|
| 29:36 | we've got the salad is Yeah. . So if you did that you |
|
| 29:40 | have to go back and do if wanted to know precisely you'd have to |
|
| 29:45 | the whole shebang. You have to their dialect and then you have to |
|
| 29:52 | their anatomy and then you have to that it actually does have a specific |
|
| 29:58 | at marker because science is actually very and it's quite competitive and advances very |
|
| 30:07 | . And if you want to stay the cutting edge of the journals that |
|
| 30:11 | publish the most recent most interesting information have to perform as many on of |
|
| 30:18 | techniques are good in the most clever that you can. So for example |
|
| 30:22 | can in these days take a transgenic which means it has been genetically manipulated |
|
| 30:30 | transgenic animal may have certain cells globe certain cells that have a specific marker |
|
| 30:38 | will show up and blown the slices in your brain and you can even |
|
| 30:43 | them with light whatever they're expressing the receptors. So there's a lot of |
|
| 30:48 | that you have to do very I'm not saying this is the only |
|
| 30:52 | or way this is the only way which you can if you do the |
|
| 30:58 | mice you still don't know their So you're assuming that because you pick |
|
| 31:04 | specific cell marker, it will be in the specific cells up that that |
|
| 31:08 | that dialect. But guess what? would still need to confirm it |
|
| 31:13 | So um you still have to do slew of experiments if you want to |
|
| 31:19 | precisely identifying a specific subtypes of Now when it comes down to these |
|
| 31:24 | to parameter cells, people will accept signatures, they seem their signatures, |
|
| 31:30 | know how they fired, they know they're located. And a lot of |
|
| 31:34 | you don't need to do additional staining order to publish some data from from |
|
| 31:40 | those cells. That's Well you it's way too many 21. and |
|
| 31:51 | thing I'd like for you to do to be able to repeat language but |
|
| 31:57 | imitated for you from these sounds exactly I did it on the exam. |
|
| 32:03 | , yes. So so practice at just get it. No, this |
|
| 32:10 | just an illustration to kind of help understand And no you don't have to |
|
| 32:17 | these 21 different subtypes of cells. take home message is that you have |
|
| 32:23 | complexity because of the inhibitory cells and have the out the complexity of the |
|
| 32:30 | cells depends on the dialect that is spoken to but the surround themselves. |
|
| 32:38 | this is a slice. Would be in their microscope like this, you |
|
| 32:42 | have to establish with the lectures and to visualize it. This was done |
|
| 32:47 | George Mason University. I did one my post docs in Virginia George mason |
|
| 32:55 | . And at that time we were four recording electrodes. And so you |
|
| 33:01 | see you have very little space. whole space is probably about one |
|
| 33:07 | So very little space to work You have these amplifier heads and electrodes |
|
| 33:13 | you are trying to place right underneath lance and touch onto the cells produce |
|
| 33:20 | same stimulus. And I guess when run out of really expensive equipment then |
|
| 33:30 | have nothing left in the lab of pen. And instead of $1000 |
|
| 33:37 | you jerry rig a pen and hot to your little pre amp that's connected |
|
| 33:45 | wired And it's usually like around nine when you do that because it's only |
|
| 33:53 | people like that do these kinds of . They are very difficult. And |
|
| 34:00 | done endless hours of these experiments have realize that for you to place a |
|
| 34:06 | in their microscope. It's not oh I'm just gonna go and take |
|
| 34:11 | mouth slice from the fridge and then going to place it under a |
|
| 34:17 | do some recordings from it, No, the brain has to be |
|
| 34:31 | . So how does this experiment look in reality You wake up at eight |
|
| 34:39 | . You go to animal room and at 8:30. You pick up your |
|
| 34:44 | and make sure that you check off in the animal protocol that you're about |
|
| 34:49 | do an experiment on, you status the mouse, you decapitate the |
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| 34:57 | and take out the brain. use slicer, it slices about 300 microm |
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| 35:04 | , about one a half inch and yourself. And you place it to |
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| 35:12 | for about half an hour to an before you place it on the |
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| 35:17 | When you place it under a microscope the environment that you provide during the |
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| 35:22 | and under the microscope is exigent nated super spinal fluid. So you're trying |
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| 35:28 | trick that slice that it's sitting in brain still and it's getting the |
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| 35:33 | Because if you put a brain or slice of the brain and the |
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| 35:37 | guess what? It has no Oxygen comes from the ones goes into |
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| 35:42 | blood vessels, goes into the micro , goes into the brains and supplies |
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| 35:48 | . And we talked about how neurons very, very sensitive to the loss |
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| 35:54 | exigent nation Hypoxia. two minutes to minutes can cause severe damage to the |
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| 36:00 | . When you have a complete loss oxygen. So to get to this |
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| 36:05 | where you are ready to turn on recording equipment and everything else is about |
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| 36:10 | hours worth of work. Now you that slice that's alive for about 10 |
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| 36:18 | And it's an animal that may cost and chemicals that make us depending on |
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| 36:27 | you do. $50 or $500. that's why I said that you have |
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| 36:34 | be very dedicated to these types of . But you learn a lot and |
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| 36:41 | build stamina just the same way the build stamina. And as a surgeon |
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| 36:49 | either wear a diaper, you don't learn how not to use the bathroom |
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| 36:52 | 8-10 hours That kind of Stamina where get up and it's 9:00 and you |
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| 36:59 | to experiment and you go home and back is hurting like how because he |
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| 37:05 | on that chair. But everything that do to your back and uh that |
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| 37:15 | into your brain actually and uh and soon be smarter. You have to |
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| 37:22 | start certain things out. You have you have to learn things, you |
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| 37:25 | to go through certain tasks and And this is the only way we |
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| 37:31 | actually start revealing the structure and But individual cells and cellular networks in |
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| 37:37 | brain. Okay, Gloria glia first start to be glue passive just passive |
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| 37:48 | support and insulate neurons but microbe leah , they're responsible for damage, repair |
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| 37:57 | clean up of damage. Astra sites another subtypes of whale cells. They're |
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| 38:04 | for some people who say housekeeping chores in general they are very much and |
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| 38:11 | involved in neurotransmitter, the neural transmission ionic uptake and neurotransmitter uptake and also |
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| 38:21 | comprise part of the blood brain barrier will discuss astro sites. There are |
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| 38:30 | glial cells and those cells guide Surono and process outgrowth. Uh They can |
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| 38:38 | serve as neuronal and glial pre So there's a very interesting stuff types |
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| 38:44 | cells will come back and talk about in the second real cells can release |
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| 38:49 | factors that are necessary for the synaptic . The formation of the synopsis for |
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| 38:56 | in normal brain function. They actively the formation of new synopsis, synapse |
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| 39:06 | , synapse function and plasticity. But cells unlike neurons that have a dialect |
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| 39:14 | action potentials and so on. Real don't produce action potentials. They have |
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| 39:23 | deep polarization is that are mostly driven calcium. They're very slow deep polarization |
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| 39:29 | action potentials. So this is the of the clear and it's also much |
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| 39:39 | language. So that should tell you neurons are very fast. Certain neurons |
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| 39:45 | produce 600 hertz, 600 spikes, action potentials Others can produce 5 1 |
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| 39:55 | potential a second are very slow and cells are evil slowly. But Just |
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| 40:04 | about what I said that certain neurons fire 600 action potentials a second. |
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| 40:11 | Hz frequency. That's very very And there's different scales of processing in |
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| 40:18 | amongst those neurons and Julia is the processing in time. Mostly driven by |
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| 40:27 | . So let's talk a little bit Before we get to the installation. |
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| 40:34 | me see if I have this uploaded your file already caused this. |
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| 40:41 | You go into your class lecture there is a folder that's called supporting |
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| 40:48 | lecture documents and then there you will some very cool things that we talked |
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| 40:53 | during classes. Either links the online , links to maybe even some articles |
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| 41:02 | are down here. Um links to talk. Here's a talk by me |
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| 41:09 | that's linked there, I think it's available and let's talk about the glial |
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| 41:15 | . And what I said is that glial cells in particular are responsible for |
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| 41:23 | for neuronal migration. So this is your folder, a link to video |
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| 41:30 | shows just that I'm not exactly that is so excited, you know. |
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| 41:41 | about that. But if you go the real video then what is portrayed |
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| 41:48 | is this radial glial cell. This glial cell is actually this line here |
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| 41:54 | looks like a rope and this is neuron that is migrating along this |
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| 42:01 | So when neurons form initially in the , they don't form everywhere. They |
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| 42:06 | formed in special parts of the And from there they migrate to their |
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| 42:10 | destinations and they occupy their final they of a starting general geographical area. |
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| 42:18 | they go through the city which is of the brain. Then they go |
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| 42:21 | the little neighborhood which could be a structure of that brain and they finally |
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| 42:26 | a mailbox which is their house but have to migrate that. And radial |
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| 42:31 | cells form cytoplasmic continuity with the migrating and provide this migration like lattice that |
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| 42:41 | four neurons to essentially use it's sort like a rope rope climbing to get |
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| 42:49 | the destination where they need to be . Yeah. I didn't have a |
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| 43:21 | video commercial in it. That's So you can see another example of |
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| 43:32 | neuronal migration of how different cells would migrating and it could be using their |
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| 43:39 | so they can also latch on to cells. And radio glial cells would |
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| 43:45 | responsible for providing some of these lattices neurons to find their final destinations. |
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| 43:54 | Which is which is very important. fact when we study cortical anatomy will |
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| 43:59 | that some of the micro columns originate the common roots, radio gangly um |
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| 44:07 | like south that guides all of the in that specific location. All |
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| 44:14 | so micro glial cells and microbes, cell dynamics Micro glial cells are responsible |
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| 44:22 | the repair when damage happens. This an example of this yellow, |
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| 44:32 | it's not yellow, it's white and seeing this wide circle here. It's |
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| 44:37 | a damage that's caused neuronal tissue. then you have a time lapse video |
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| 44:43 | this is 10 micro meters. The 10 micrometers. And so what you're |
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| 44:49 | is that following the damages damage, immediately see the outgrowth of the micro |
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| 44:56 | processes toward the side of the And actually over time the selma's the |
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| 45:04 | surrounding for the process is also more and even the soma start migrating forward |
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| 45:10 | side of the injury. So michael cells are the most dynamic cellular elements |
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| 45:19 | the brain actually can move through the tissue and mature brains especially following the |
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| 45:26 | . So the process is first followed the displacement of the actual cell |
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| 45:38 | Mhm. Yes. Yeah, whatever migrate. Uh Is that because like |
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| 45:55 | students, another, it's a congregation it. It's an excellent question. |
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| 46:09 | a very complicated question and people are neurodevelopmental and developmental cellular biology. Would |
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| 46:17 | cursing my answer right now, but eyes will tell you is very |
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| 46:22 | So they can't curse much at But it would have to do with |
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| 46:27 | and chemo sensor accuse there is an and I'm not certain what would be |
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| 46:34 | once a cell already gets there and already positioned there, the other cells |
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| 46:41 | they going to know not to go anymore to compete for that space? |
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| 46:46 | a great question. I don't even if there is an exact answer of |
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| 46:51 | that happens or exact answer on maybe limitations from how many cells can be |
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| 46:59 | one area or can be provided by same radio. Well guided by the |
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| 47:04 | radio real cells. But that's a good question. I don't have an |
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| 47:09 | to this is definitely the queues The trophy cues. Uh schema sort |
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| 47:17 | a touch sound cell recognition environment. all of these things will play a |
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| 47:23 | of it. Okay, um Glial are very important for providing Miley Nation |
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| 47:32 | neurons in the periphery. It's a south where one Schwann cell will form |
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| 47:38 | individual Meilin segment on the peripheral nerves the C. N. S. |
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| 47:46 | myelin is formed by illegal gender size the legal gender size will have multiple |
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| 47:53 | in each one of these processes can around and form an individual myelin |
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| 48:02 | the myelin sheath unit along the south the breaks in the mill in. |
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| 48:09 | not continuous. Our nodes of ranveer have high densities of sodium and potassium |
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| 48:16 | necessary to reproduce or the action So ostracized these astro city processes. |
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| 48:29 | this is the Myelin Nation of the . And you can see that Myelin |
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| 48:32 | takes place sort of like ring like that gets wrapped around and wrapped around |
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| 48:38 | wrapped around and wrapped around the These are the brakes, the nuns |
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| 48:44 | round beer and a legal emphasize here the for the CNN. S. |
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| 48:53 | , so today we're gonna introduce another . But in general today we're going |
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| 49:01 | introduce a little bit about Myelin You have these Myelin basic proteins or |
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| 49:08 | that are in control of the precise sheathing and Myelin Nation and compaction around |
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| 49:18 | axles. You have several related Examples are Macmillan associated like a protein |
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| 49:27 | would be responsible for initiation of my Also for cell to cell recognition because |
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| 49:33 | liquid underside has to recognize another cell its acts on as a friendly one |
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| 49:39 | order to Myelin ate it. if you have abnormal milder nation, |
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| 49:56 | , you can have inflammation and even dim elimination or loss of myelin around |
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| 50:06 | . And so loss of Marlon around would be like stripping this wire of |
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| 50:14 | plastic that surrounds it. So the becomes wiki um, there's a model |
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| 50:25 | multiple sclerosis as referred to as sugar . And we'll talk about why. |
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| 50:30 | so the disease that we will introduce multiple sclerosis. And there's a dim |
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| 50:36 | disease. And one of the important of this disease is an autoimmune |
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| 50:42 | which means that if the body starts Myelin as its own enemy and starts |
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| 50:51 | eliminating its own narrows multiple sclerosis as you can see, this is |
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| 50:58 | , fully Myelin ated accents. And you have de Meira Nation. You |
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| 51:03 | produce that in a shiver mouse It's a transgenic mouse model. You |
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| 51:09 | a mutation in chromosome 18. That's of the mutations uh, can |
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| 51:17 | and is responsible for multiple sclerosis. now you have a genetic component of |
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| 51:22 | sclerosis. The symptoms of multiple The pathology is demolished nation, the |
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| 51:30 | that is on the outside the symptoms tremors, convulsions and spasms. Or |
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| 51:36 | could be very painful, but it's just in the periphery, it's also |
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| 51:42 | the brain. So if you think pain in your hands, the denomination |
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| 51:47 | spasms in your hand, you can equivalent spasms and you see a national |
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| 51:52 | networks family communicating with each other. It's a recessive, genetically recessive. |
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| 51:59 | you need to badal eels in order have multiple sclerosis. Yeah. This |
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| 52:12 | a normal mouse or the abundance This is shiver mutant that has an |
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| 52:18 | nation. And the reason why it's to shiver, it has these |
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| 52:24 | It's almost like shivers, entire body . These animals. You can transfer |
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| 52:31 | normal gene and improve the Myelin There's an experiment we can transfer act |
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| 52:37 | gene and improving my relation uh multiple again. Alzheimer's disease is aging disease |
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| 52:51 | and up the incidents goes up tremendously , fragile lacks is a developmental neuro |
|
| 53:04 | disorder. Uh huh. Multiple The onset or the prevalence of the |
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| 53:15 | starting from 30s. So it is a developmental, it's not an aging |
|
| 53:24 | . When you think the reason why say that is you always have to |
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| 53:27 | about. When does that disease Of course you can have some |
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| 53:32 | S. cases as early as but typically the onset is 30 years |
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| 53:39 | older. And the symptoms when you about uh periphery traumas convulsions with |
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| 53:50 | like I said, spasms which is up of the muscle. So an |
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| 53:54 | to essentially like having a muscle But it comes from not from physical |
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| 54:02 | but from desalination and abnormal signaling an signals, action potentials that are being |
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| 54:10 | or not sent along different pathways. . Mhm. The speed using cell |
|
| 54:28 | . That's a very good question. far as I understand, it starts |
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| 54:33 | the legal Denver cites the self the in itself as a foreign as a |
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| 54:40 | object. Who? Yes. You know in the peripheral because it |
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| 54:51 | also target foreign cells. Yeah. . Yeah. Yeah. The french |
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| 55:14 | . What exactly? That's also a question. But uh I'll have to |
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| 55:23 | back to you about that. You the most interesting questions and they're quite |
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| 55:31 | and uh injecting the gene, obviously making more of something and in this |
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| 55:39 | I think you're making more prudent rather more of the cells. But I'd |
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| 55:44 | to check and that would make Also maybe in in relation to the |
|
| 55:50 | question as well after I checked. by the way, did you find |
|
| 55:55 | what is golgi stain steaming? Uh . It's kind of it takes up |
|
| 56:01 | . It takes up everywhere. So don't think there is a very good |
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| 56:06 | for that. But if anybody finds , let me know the other disease |
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| 56:14 | is related to abnormal Myelin nation is you have too much of the peripheral |
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| 56:22 | protein man PMP 22. You have gene duplication in this case in chromosome |
|
| 56:31 | . Too much of the PMP to you can pick up actually really |
|
| 56:37 | That results in the shark got married disease. And shark got married tooth |
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| 56:45 | is a developmental disease. That means onset of this demon pollination happens early |
|
| 56:54 | . And the symptomology and the pathology this case can be seen on the |
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| 57:01 | because of the abnormal myelin nation. signals don't get some properly to the |
|
| 57:09 | in the periphery. Uh The signals not being sent in the muscles |
|
| 57:18 | Then you don't have activation of those and the bones shape around and you |
|
| 57:24 | the form. It is in the you have deformities in the bone which |
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| 57:28 | impaired gait. In addition to the . Formative. And there is no |
|
| 57:35 | for shark got married tooth but if very early on. They can be |
|
| 57:42 | ist. It can be placed around parts like the ankles and the knees |
|
| 57:47 | trying to prevent the deformation and help individual to with their motor function and |
|
| 57:54 | movement ability. So um this would in the periphery. Now, if |
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| 58:04 | overview all of the cells. This the best slide, you can see |
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| 58:09 | you have a legal dentist sites and CMS and provide mylan. You have |
|
| 58:16 | that interact with the synopsis and control transmission and neurons. You also have |
|
| 58:23 | that project onto these capital reason form feed processes for the blood brain barrier |
|
| 58:31 | the micro glial cells the smallest and most dynamic elements that we discussed. |
|
| 58:37 | have this interstitial space between the cells from the cerebrospinal fluid space by penn |
|
| 58:45 | cells of the pen. Dermal cells also interesting type of uh send them |
|
| 58:51 | south. That can potentially be a to both. It can be a |
|
| 58:58 | cell that becomes see them there on glia in some instances. So. |
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| 59:03 | this is an overview of all of glial cells attitude that we've discussed here |
|
| 59:10 | the last thing that we'll talk about is the blood brain barrier which we |
|
| 59:14 | up in the very first lecture. you recall the anatomy of the blood |
|
| 59:20 | barriers that you have in the ethereal which are blood vessel cells, blood |
|
| 59:25 | walls and they have tight junctions in them. So things cannot really pass |
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| 59:32 | tight junctions unless they allowed to pass tight junctions that parasites and the Astros |
|
| 59:41 | processes. So the final component of blood brain barrier is the extra sides |
|
| 59:48 | collectively the blood brain barrier will control passes from the blood into the |
|
| 59:55 | This is a blessing. But it's a big therapeutic challenge. So you |
|
| 60:03 | often see some commercials. Let's see commercial can we see uh mm mhm |
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| 60:30 | not promoting Cymbalta just randomly dialed in for anxiety. It's mm Rachel's |
|
| 60:47 | So yeah yeah. You are really company. Wait anyways a a |
|
| 61:47 | You're taking a medication for depression or a neurological condition. Apple. |
|
| 61:53 | There is something else and you have liver problems. Why is that? |
|
| 61:58 | have a lot of some drug that processed and metabolized by the liver. |
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| 62:02 | in your body because in order for to treat depression and severe depression, |
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| 62:07 | have to get enough of the drug the brain and that drug has to |
|
| 62:11 | through what the blood brain barrier. if it's a really good drug, |
|
| 62:17 | will pass through the blood brain barrier easily and will have minimal side effects |
|
| 62:22 | the periphery including on the um the and deliver metabolism. Okay, let's |
|
| 62:30 | . Some more abdominal pain, yellowing eyes. I don't know. Constipation |
|
| 62:57 | nothing to do with anxiety. it has to deal with the treatment |
|
| 63:03 | the disorder. But you're having all these peripheral effects. And so this |
|
| 63:08 | be referred to side effects. I'm like criticizing this. But I'm just |
|
| 63:17 | sharing an example of any drug commercial you will see. Um We'll talk |
|
| 63:26 | side effects. And when you look the commercials for neuro drugs, neurological |
|
| 63:33 | , drugs for epilepsy drugs. You have a lot of these common side |
|
| 63:38 | , deliver problems. You have abdominal , nausea, vomiting or have |
|
| 63:43 | You take opiates to treat pain and have constipation and then you have a |
|
| 63:49 | medicine that's treating opioid induced constipation to the constipation that's induced from opiates. |
|
| 63:55 | a it's a lot of stuff that's on in the body with chemicals. |
|
| 64:01 | so this is a challenge. It's blessing, right? Because if you |
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| 64:05 | stuff in the blood and it just into the brain, that would be |
|
| 64:09 | . But it's also a challenge from neurodegenerative drug development perspective. So thinking |
|
| 64:18 | really effective drugs is something that would low dosage, something that would pass |
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| 64:22 | the blood brain barrier and ideally after with target specific self, sometimes ideal |
|
| 64:31 | specific networks that you can get to the brain and such. Okay, |
|
| 64:37 | we'll end our lecture today. I you a good afternoon and we'll be |
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| 64:43 | here again on monday to continue. a short week this week it seems |
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| 64:49 | so enjoy it. Mhm. |
|
