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00:01 | We could lecture four of neuroscience and we talked about the site of skeletal |
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00:07 | , we're going to actually introduce the . Our first neurological disorder that we |
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00:12 | in the scores and that is Alzheimer's . Right. And so you'll see |
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00:19 | this is related to Cida scalp elements just a minute. But before we |
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00:23 | that and talk about the mechanisms or cellular mechanisms, the pathology of the |
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00:29 | . With this slide illustrates illustrates that marks of the pathology of Alzheimer's |
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00:37 | And when you think about alzheimer's you have to start thinking about it |
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00:43 | many different angles and many different So you may have a perspective of |
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00:52 | disease where you have experience or you somebody or you have somebody in the |
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00:59 | that have suffered has suffered this suffering Alzheimer's disease. And when you think |
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01:09 | Alzheimer's disease, the first thing you to think about, Well what is |
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01:15 | prevalence see and what is the occurrence this disease over a different lifespan. |
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01:23 | is Alzheimer's disease, a developmental It's Alzheimer's disease disorder that usually has |
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01:30 | typical onset in the 20s or as disease, uh an aging person |
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01:40 | And the cases with Alzheimer's is that is much higher onset and occurrence of |
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01:46 | disease if you're 55 and over. , so there's certain neurological disorders that |
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01:54 | manifest themselves early in life, may in the first few days of |
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02:00 | even there are other neurological disorders that and unfold themselves Into early Adulthood and |
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02:10 | 20s and 30s and Alzheimer's disease is dementia and alzheimer's dementia is a form |
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02:18 | dementia, it's not a part of aging And Alzheimer's disease is most prevalent |
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02:27 | the population of 55 years and Mhm. So when you think about |
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02:36 | disease, the next thing is you associate certain neurological disorders with symptomology and |
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02:49 | , for example, is a So if you have an infection or |
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02:56 | infection, that's not a symptom, symptom is a headache, it's a |
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03:02 | nose loss of smell, right? with Alzheimer's disease, when you think |
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03:08 | patients that have Alzheimer's disease, what to mind memory loss. So this |
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03:19 | some of the early symptomology that a experiences with Alzheimer's disease. Not the |
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03:26 | symptomology, it's an early symptomology. recommend you take notes on Alzheimer's disease |
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03:33 | also leave some space because we'll come and talk about in the second section |
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03:39 | the course as well. When we about neurotransmitter systems and we'll talk about |
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03:44 | therapy or common medications for Alzheimer's So now memory loss. Disorientation, |
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03:52 | disorientation uh time. Disorientation and then is the early stages of the disease |
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04:03 | what typically happens with many diseases is is called progression, they progress and |
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04:13 | as the disease progresses the symptomology gets and more severe. So if your |
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04:25 | stages early onset of Alzheimer's disease, may be a significant loss of short |
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04:33 | memory a little bit later, there's loss of both short term and long |
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04:38 | memory and then uh severe parts of disease. When it progresses to the |
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04:46 | stages of the disease, you have neuro degeneration in the brain that leads |
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04:54 | essentially your brain not being capable of care of your body leading to |
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05:01 | So many different symptoms along the way the progression of this disease right |
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05:10 | So these are some of the important that we're discussing right the occurrence or |
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05:16 | it is likely that people have Alzheimer's . We're talking about the onset of |
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05:23 | disease 55 plus, we're talking about symptoms. So on good notes to |
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05:33 | progression of the disease into more advanced more severe stages and that the severe |
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05:40 | of the disease, you have a pathological hallmarks of Alzheimer's disease. And |
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05:47 | particular on a cellular level inside the you have formation of neuro february |
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05:58 | We just talked about cyber skeletal elements those neural february tangles inside the south |
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06:04 | actually start interfering with the cell transport external transport and also with the normal |
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06:13 | of the south. In general So we talked about the fact how |
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06:18 | have these micro tubular highways and how have the site of skeletal elements involved |
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06:24 | the transport involved in the support of structure involved in the plasticity and rearrangements |
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06:31 | Nous rearrangements in the structure. So the cells and outside the cells. |
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06:39 | hallmark of cellular Alzheimer's disease pathology. formation of amyloid plaques also called beta |
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06:48 | plaques. Also called senile plaques or plaques sometimes. But these are abnormal |
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06:58 | of a protein that gets cleaved off membrane. Amyloid precursor protein and aggregation |
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07:09 | forms these amyloid plaques that become calcified they're on the outside of the cells |
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07:16 | they're also very dangerous to function normal of neurons. They can move and |
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07:23 | so they're not stationary. And typically Alzheimer's disease there is occurrence of these |
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07:32 | in certain areas of the brain such the hippocampus that we'll talk about later |
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07:37 | hippocampus is a structure that is involved memory and semantic memory or storytelling |
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07:44 | So these plaques can migrate throughout the . They can be located in many |
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07:51 | locations and as they become located closer closer to neurons and start interfering with |
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08:00 | ax on and the ability of neurons produce action potentials reliable. So they |
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08:07 | interfering basically in communication, affecting the between different generals. This is the |
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08:17 | level on the south and south This is the macroscopic level of gross |
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08:27 | uh changes that you would see as compare severe Alzheimer's brave to a healthy |
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08:37 | here and what is happening is there a significant neuro degeneration, there is |
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08:47 | of neurons. There is a significant of the gray matter in particular and |
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08:54 | overall decrease in the volume and overall of the whole cerebrum. So this |
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09:03 | on a macroscopic level. And uh would observe the plaques and you would |
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09:12 | such severe anatomical changes postmortem. Some these you would be able to observe |
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09:20 | as a person is having advanced stages Alzheimer's disease. But quite often there's |
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09:27 | comparison to what the person's brain looked 15 years ago, 10 years |
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09:33 | before the onset of the disease. , okay, so this is all |
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09:39 | things we're not talking today about the will come back and talk about neurotransmitter |
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09:45 | in particular settle coding that's involved in disease and that's affected the most. |
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09:52 | we'll talk about the medications that are used to treat Alzheimer's disease. |
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09:59 | so this I'm gonna share with you this afternoon the slide is going to |
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10:03 | incorporated in the class material. So just forgot to share the extension and |
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10:10 | go back to swat's here. So what are some of the other |
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10:25 | that are different about neurons that have grads and they have them exposed and |
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10:29 | about? They have axons. Axons collaterals axons where the action potential is |
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10:37 | to be produced. This axon is to be my eliminated. If the |
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10:43 | terminal, you'll have a lot of , you'll have the vesicles that are |
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10:47 | with the neurotransmitters and located what we in the active zones, pre synaptic |
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10:52 | they will release the neurotransmitter in the collapse and the boston optical. You |
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10:58 | post synaptic done right here and what call post synaptic densities of post synaptic |
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11:04 | that will be interacting with these Liggins these chemicals that are being released from |
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11:10 | vesicles pre synaptic aly. So uh axons themselves apart from producing the action |
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11:23 | , they also are involved in acts plasma transport. And there are two |
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11:28 | of transport. There's a slow transport there's fast acts of plasma transport. |
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11:35 | under slow transport have tied up axon the early days when people were able |
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11:42 | finally isolate little microscope and you can do it with the naked eye |
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11:49 | Giant axon, it's about one millimeter diameter. They would actually take a |
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11:55 | like a piece of string and they tie around the axon, they would |
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12:02 | the dye and then tie it around axon and they would monitor how long |
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12:07 | it take for this guy to travel the location of the injection all the |
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12:12 | to the distance across the axon. this is tied up axon. They |
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12:18 | the slugs of plasma transport was discovered that which is about 1 to 10 |
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12:23 | a day. Some actions can be , depends where they are located but |
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12:28 | can be on the order of sometimes tens of centimeters and lights or |
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12:33 | longer. We also have fast ectoplasmic and fast ectoplasmic transport was demonstrated using |
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12:42 | labeled click assets and the speed of is 1000 a day. So 10 |
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12:53 | a centimeter Alright and 1000. I it's a meter, so it's a |
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13:03 | a day. And as we talked micro tubules serving sort of as the |
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13:09 | for this transport. You need to the delivery mechanisms that you need to |
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13:17 | like delivery trucks that right along these . And so these are the motors |
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13:25 | that will carry information in the interrogated interrogators from the soma into the |
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13:32 | And there's another um motor protein die that will be responsible for carrying different |
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13:44 | in the retrograde direction which is from periphery and into this home. |
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13:51 | so we have both kinds of It would be really bad if you |
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13:57 | only one way a highway that had direction from here into uh into Galvis |
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14:04 | and back. Although maybe not so . But you know, so it's |
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14:09 | it's a bidirectional transportation and this kind a transport can be taken advantage off |
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14:19 | you want to trace the connectivity So, so far we talked about |
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14:25 | stains of the dies for neurons. talked about the Golgi stain which was |
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14:32 | for neurons and only a fraction of to cup Golgi stain and revealed all |
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14:37 | the precise morphology of those neurons that taken up Golgi stain. We talked |
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14:43 | missile stain. The missile stain. said it stained all of the um |
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14:49 | neurons and glial cells but did not the precise anatomy or morphology of the |
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14:56 | but rather the cider architectural arrangements of different cell populations. Right? And |
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15:03 | so this is the individual cells. we also want to know how different |
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15:10 | of neurons and how from the periphery different parts of the C. |
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15:14 | S. We have connections. And way to do that is to take |
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15:20 | of these anterograde and retrograde transport that have and use tracers. So there's |
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15:29 | tracers that are mentioned here. There's Peroxide Days which is a chemical, |
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15:36 | herpes virus and rabies virus which are . If you look at this diagram |
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15:42 | shows that you can take horseradish peroxide it's like a diet. You can |
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15:47 | it and let's say you're interested to what neurons are contacting this particular patch |
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15:55 | the brain for this particular patch of muscle with this particular patch of the |
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16:00 | . So you will inject your dye this particular patch let's say of the |
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16:07 | . And then using in this case transport which is from the periphery into |
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16:14 | Omagh's you would have in this case days later a very nice steam from |
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16:22 | area to which you injected the tracer where that trace of travels into the |
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16:29 | . So now you know that it's particular neuronal network that is connected. |
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16:36 | accents of this network are located here nerve endings because it's the retrograde |
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16:43 | So it gets picked up by the and retrograde transported into the summit. |
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16:49 | that's quite important if you want to the connectivity between different neuronal populations. |
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16:57 | I and as I said from periphery uh periphery into the cns. Some |
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17:05 | the viruses are also capable of retrograde like herpes and rabies viruses. And |
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17:13 | can be used for scientific scientific tools labeling for tracing and revealing connectivity in |
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17:20 | brain. Some of the viruses that talk later. And of course when |
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17:24 | talk about some out of sensitive core we will talk about herpes simplex virus |
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17:32 | that is the virus that's capable of . It's capable of interrogate and retrograde |
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17:39 | at different times during its lifespan of virus. So we'll come back and |
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17:47 | about this a little bit more. these are useful tools if you want |
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17:51 | demonstrate a specific connectivity, trace the connectivity between different parts of the brain |
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17:58 | the peripheral veins in the brain. , so we also know that neurons |
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18:07 | endowed with this unique anatomy of having only really complex branches and branches and |
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18:15 | but on the down drives having really arrangements of the great its spine. |
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18:21 | talked about the fact that these dendritic are the points of contact and this |
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18:27 | pre synaptic south. This is the synaptic tax on with the red vesicles |
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18:32 | with neurotransmitter chemicals. And this is synaptic densities of the dem drive. |
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18:38 | this is Ridic spine has here mitochondria and has a smooth into plasma particular |
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18:46 | stores. Uh and so they come different shapes but they do have a |
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18:53 | arrangement on the dendrites. And as talked about the project sponsor the most |
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19:00 | elements. So when you think about of skeletal rearrangements, rearrangements in the |
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19:06 | of the membrane, the fluid mosaic of the membrane being migrated into by |
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19:13 | proteins or different proteins inserted into the membrane. So as you strengthen the |
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19:21 | between the pre synaptic and the possum south. This synapse difficulty strengthens and |
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19:27 | may even grow larger. If there no communication between these neurons, this |
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19:36 | neuron then the spine may eventually actually in size and its effectivity or its |
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19:44 | is not not going to be as . So you can potentially eight. |
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19:48 | spines you can have better efficacy at pre synaptic possum communication or you can |
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19:55 | the spines which is called depression of in this pre synaptic synaptic communication. |
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20:04 | as we're born we actually have a more synaptic connectivity and we have a |
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20:10 | more synapses than we end up having we are adults who were developed |
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20:16 | everything is connected to everything as our are developing and as we're exposed to |
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20:25 | environmental sensory cues and undergo certain genetic for the development and assembly of the |
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20:35 | nervous system. As all of this . The dendritic spines are being |
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20:43 | meaning that you are losing synopsis is you're born with a lot more synopsis |
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20:48 | you end up when you're adult. this connectivity in the developing young brains |
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20:54 | quite non specific. Like I everything is connected to everything, but |
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20:57 | don't want that in the brain and don't have that in the adult |
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21:01 | So we have specific structures connected to specific structures responsible for specific functions. |
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21:09 | these are the most plastic elements. highest levels of plasticity will be found |
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21:15 | intervening spines. If you're learning new , you're strengthening existing good expanse of |
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21:22 | new ones, developing new synaptic connections the expense of maybe some older |
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21:29 | Because we have finite amount of information space in the brain that we can |
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21:35 | and have. Uh Now this process plasticity and anatomical and functional rearrangements are |
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21:52 | dependent processes. So that's why we it activity and environment dependent plasticity. |
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22:01 | it also is dependent on the genetics normal genetic code for the development |
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22:10 | These dendritic spines because they have they have scr right there and they |
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22:16 | polarized. So more complex systems, is somewhat biochemically independence functionally biochemical |
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22:25 | small units that can do a especially post translation locally at the level |
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22:32 | the spine. Not even the dendritic or the selma. Okay, so |
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22:39 | second uh disease that we're going to about today is actually related to what |
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22:49 | talking about the dendritic spine structure. disease is called fragile X. Fragile |
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23:03 | falls under autism spectrum disorders. So are multiple disorders, multiple symptoms that |
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23:21 | essentially classified under this general umbrella. or less of autism spectrum disorders. |
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23:30 | , fragile acts and autism. Uh talking fragile X and neurological disorder. |
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23:39 | talked about Alzheimer's disease and I asked , well, what do you know |
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23:43 | Alzheimer's disease? Memory loss and aging . When you think about autism, |
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23:51 | you think about aging population? Do think about middle aged people? Do |
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23:56 | think about developing Children? So, Children and that would be the most |
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24:03 | onset or when that disease starts manage itself outwardly with the symptomology ease of |
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24:12 | disease. In this case, we're going to talk about the symptomology as |
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24:17 | for autism or fragile. Actually going talk about this particular cellular mechanism fragile |
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24:24 | as a genetic disorder. So, didn't talk about the causes of Alzheimer's |
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24:32 | , but the cause of fragile life a genetic cause it's linked to the |
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24:38 | chromosome where it has a fragile It occurs both in developing girls and |
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24:49 | boys, but it is more severe boys than girls. There is uh |
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24:58 | outward appearance of this disease where Children have abnormally long faces and ears and |
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25:09 | they may have also a smile. they're they're, you know, they |
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25:14 | certain outward facial features that indicate fragile . But our main purpose of highlighting |
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25:23 | X. To talk about the fact fragile X is a mental representation, |
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25:33 | X is a mental reservation. And of the cellular anatomical features that you |
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25:40 | seem fragile acts as well as an models of fragile acts that affect the |
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25:46 | gene. We know it's called the gene. This gene impairment in that |
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25:55 | will cause the abnormal spine monogamy. you can see that compared to then |
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26:03 | from a normal in front, which more or less uniform density distribution of |
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26:10 | spines and the types of the shapes the sponsor we already discussed than study |
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26:16 | white quality. This dendrite now is spines and large swats of this stand |
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26:26 | process All of the spine seem to having one shape only. Then all |
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26:33 | them seem to be really long. what that does is your learning is |
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26:40 | affects the synaptic connectivity and that affects communication between neurons. Therefore it affects |
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26:47 | learning and re leads to learning disabilities mental degradation as well. Now, |
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26:55 | that have fragile acts besides having the , which is a symptom right? |
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27:05 | would also quite often have epilepsy and . So Children that have fragile |
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27:15 | why alpha will have epilepsy. What that? Epilepsy is another neurological disorder |
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27:28 | manifests itself in seizures, these are I call electrical storms in the brain |
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27:38 | have many different ways that they can themselves. The motor component, tonic |
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27:44 | , no motor component, emotional component so on. The number. When |
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27:48 | talked about Canadians gauge and we talked temporal lobe and we said about how |
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27:54 | are certain areas of the brain that involved in emotional processing and on the |
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28:00 | . I had micro stimulation and I temporal lobe epilepsy with micro stimulation. |
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28:06 | said if you stimulate certain parts of brain around the temporal lobe you will |
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28:10 | a certain emotional response and people that epilepsy and have that particular part of |
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28:16 | brain generating seizures. They will also a very strong emotional response. So |
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28:22 | different ways in which seizures manifest And we're gonna talk about epilepsy later |
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28:27 | this course, actually in greater So what is epilepsy have to do |
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28:32 | fragile X is a is also a question. Well, you have neuro |
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28:41 | , you having proper connectivity and neurons it didn't take spines that abnormal you |
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28:48 | generating seizures and epilepsy becomes a co . Oh morbidity with this co |
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29:03 | It's something that can kill you. yes, fragile X and mental renovation |
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29:12 | result in a shorter lifespan because of neurological disorder. If you develop. |
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29:20 | not all Children will have seizures and collapsing. About a third of all |
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29:25 | the Children will have seizures in Asi that half fragile acts. But |
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29:30 | you develop seizures in epilepsy that becomes morbidity independently of the dendritic spine |
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29:41 | their connectivity and mental reputation independently of . Now you have another disease process |
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29:49 | is linked to your first disease and disease manifesting in seizures is also causing |
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29:56 | neural degeneration and it essentially is doing it's has the potential to kill you |
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30:04 | . Okay, so your lifespan, you have one serious for mobility too |
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30:11 | , it could be other things are related to the brain. For |
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30:16 | failure of some organs that are related the medications that somebody is taking for |
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30:22 | years and chemicals that lead to another . That basically, now if you |
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30:29 | 23 comorbidities, they can all lead a shorter lifespan. Now, if |
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30:38 | look at this diagram here, this a neuron and everywhere you're seeing green |
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30:44 | these green pancakes, these are glutamate . So these are excitatory glutamate synopsis |
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30:52 | you can see that a single as we discussed in half thousands, |
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30:57 | even hundreds of thousands of synapses on single unit. And all of these |
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31:03 | publications that are shown in orange, standing for Gaba receptor, the Gaba |
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31:11 | is gabba synapses which are inhibitory So in other words, out of |
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31:20 | thousands of dendritic spines, a lot them are going to be excitatory, |
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31:27 | lot of them are going to be neurons have to compute that information that |
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31:34 | in on the barrages of tens of of thousands of active synapses that are |
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31:42 | excitatory de polarize. The cell will to make the cell fired action potential |
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31:47 | communicate that information to the other interconnected and these inhibitory cells that are going |
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31:54 | release gap that are going to hyper these neurons and we'll try to keep |
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31:59 | away from producing an action potential and information. So now this neuron will |
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32:06 | to integrate this information within milliseconds and is excited enough producer action potential. |
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32:14 | quite often what happens when you have connectivity in this case? It's a |
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32:21 | cause uh and you have abnormal formation dendritic spines. Of course it leads |
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32:29 | learning and mental disabilities, but in it also causes an imbalance between excitation |
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32:38 | inhibition. Quite often excitation takes over there isn't enough inhibition. And when |
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32:46 | scale tells stored excitation, the person more likely to start having seizures and |
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32:55 | epilepsy as a co morbidity in the . So what are some of the |
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33:01 | questions about this fragile likes is an spectrum disorder is a mental retardation developmental |
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33:10 | ? It has co morbidity quite often epilepsy and seizures. It manifests itself |
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33:16 | the cellular level as the spine abnormality we're seeing here in this diagram. |
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33:28 | in general neurons will have four functional . They will have an input |
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33:34 | They will have the integrative component to . Yeah in part in part the |
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33:49 | complex the processes, the more complex the native trees are, the more |
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33:54 | you will have more extensive, the likely you will have more synapses. |
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33:59 | see that in in a few slides completed themselves. So now this is |
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34:06 | integrated region. So the soma. whatever inputs the neurons receive they can |
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34:12 | inputs on the soma. They can . Most of the inputs will come |
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34:15 | on the dendrites and spines, neuron integrate that information. The soma and |
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34:21 | initial segment will produce action and then electricity will be generated and will be |
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34:30 | down the axon which is my And then this axon can communicate information |
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34:37 | another neuron and can contact the muscle or even the capillary. So this |
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34:44 | the output region and this is the terminals where you have the neurotransmitter |
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34:52 | Now as you can see that some the south actually don't have the rights |
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34:57 | have to axons. This is a neuron of the dorsal root ganglion of |
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35:04 | spinal cord that has a peripheral axon goes into the skin piece of the |
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35:11 | for information that sends that information into selma selma integrates it and then the |
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35:18 | axon will send information into the spinal proper to excite the motor mirror. |
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35:25 | ? So there are variations. But are four functional regions. Now if |
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35:34 | talking about excitation and inhibition then you roughly subdivide the brain into excitatory neurons |
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35:42 | inhibiting them. And what will unravel the next half an hour to an |
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35:50 | is the fact that there is a of different subtypes of these neurons. |
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35:55 | have maybe 150 different subtypes of We're gonna study a few of |
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36:02 | We have maybe six are so Some types of glial cells and we'll |
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36:09 | about most of their functions too. how can we tell one subtype subtype |
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36:18 | from subtype 57. How did we that? They're all different subtypes. |
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36:26 | do they have to be in order be different? Do they have to |
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36:31 | look differently? They have to live different places or it's altogether their |
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36:36 | the connectivity the excitability. Were they to inhibitory with their projection neurons or |
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36:42 | they're staying locally in the network. we have divisions or classifications of neurons |
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36:52 | are based um morphology purely. You stay in many different south and you |
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36:58 | see that a lot of invertebrate neurons be you know Poland it means to |
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37:03 | one pole in this case is just north pole in this case it's a |
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37:07 | South to dendrite axon and then it so it's invertebrates and we're not gonna |
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37:13 | the cells much bipolar cell this is cell we're going to look at in |
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37:19 | retina in the retinal serving and bipolar has two poles, the north pole |
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37:26 | the south pole, the north That has a done drive and the |
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37:29 | pole. It has an accent. you have pseudo unit polar selves and |
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37:35 | unit polar cells. Ah This peripheral and the central accent that we talked |
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37:43 | . This is the dorsal root ganglion , the sensory neuron that projects into |
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37:48 | spinal cord. And then we have variety of multipolar cells. That means |
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37:57 | south have the north pole, the pole, northeast, northwest, |
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38:02 | southwest and everything in between multiple poles the processes and branching that goes all |
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38:10 | Now. This may answer the question you had earlier Recent neurons, motor |
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38:17 | of the spinal cord that have about synapses. But these cells which are |
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38:24 | into the cells of the cerebellum, little structure in the back of the |
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38:30 | , wow, it looks like it bushy Tree and it has really complex |
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38:40 | and rearrangements of these processes. And cells can have up 250,000 synapses. |
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38:49 | the more extensive uh The processes have really increase the more likely there are |
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38:57 | synapses that are being born in those cells in the middle. We have |
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39:04 | parameter cell of the hippocampus that we're come back and talk about the cell |
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39:11 | later in just a few minutes. it's called the parameter sound because it |
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39:19 | the look of the pyramid. It a base with the basil Denver |
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39:26 | it has the top or the So off the apex of the cell |
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39:33 | you have the abaco Denver ride and the base you also have the axon |
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39:38 | sends out. These are parameter We'll discuss this later today as |
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39:45 | Now some of the neurons are spiny others our spine. So that means |
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39:54 | in every science and the neuroscience or to all of the rules. So |
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39:58 | we're talking about the unique features of of having the spines, some neurons |
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40:03 | have spines um there's other exceptions to rules as we're learning. Especially as |
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40:10 | learning about the classification of bearings. me. Oh well, sponsors only |
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40:20 | side of the synaptic connectivity. They form synopsis on the soma. As |
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40:26 | can form synopsis directly in the dendritic . They can even form synopsis on |
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40:32 | accidents in some rare occasions. So the most part, the dendritic spines |
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40:38 | be the most common side of synaptic between two selves. Three synoptic |
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40:45 | Okay, so this kind of explanation not sufficient enough for us to, |
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40:54 | boy to derive 150 different subtypes of . We need a lot more information |
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41:04 | order to sub classify the cells further out really press hard. So some |
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41:19 | these cells are what we call projection . So the parameter cells excited for |
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41:27 | cells and that is difficult that these gonna be excited for parameter cells. |
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41:33 | projection neurons that means that they are in some part of the brain and |
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41:39 | going to project into the other part the brain. So parameter cells will |
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41:47 | this information Between different structures. That's they're called projection sells the project from |
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41:55 | area to another area. And as standard rule the excitatory projection cells. |
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42:03 | most of the projection cells excitatory parameter are excitatory cells. It needs to |
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42:10 | Ludin eight. Then there are a of cells that stay locally within these |
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42:21 | and they target each other or they parameter cells and they communicate with each |
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42:30 | but their axons don't exit out of network. So there refer to inter |
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42:38 | a lot of times local into For the most part these local inter |
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42:46 | are inhibitory cells and that means that are releasing Gabba and but they're doing |
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42:59 | locally and the excitatory cells are projecting . Excitatory cells also can talk to |
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43:07 | other within these networks so they can locally excitatory cells but they will project |
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43:14 | information long distances into the adjacent neuronal . This is the distinction between projection |
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43:23 | and local inter neurons based on connectivity on excitability glutamate excitatory cell gaba, |
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43:31 | inhibitory cell And then sell specific We all know that a slightly different |
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43:39 | of genes is expressed by these what call 150 different subtypes of cells. |
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43:44 | so we need to utilize techniques such immuno histology and history chemistry in order |
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43:51 | precisely reveal a specific subtype of that . Some cells will have neurotransmitters such |
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44:00 | Gaba and glutamate. Other selves will be releasing other neurotransmitters such as acetylcholine |
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44:07 | dopamine. They also can co express co release neuro peptides. And we'll |
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44:13 | about this in a little bit as . Maybe next lecture. Most |
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44:19 | neurons can produce action potentials. And finally in 1939 there was a first |
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44:27 | recording of the action potential. Uh was equipment that was circuits that were |
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44:34 | enough and the silla scope was fast that was actually concurred with some of |
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44:38 | engineering development and the military and particularly naval engineering. And so the fastest |
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44:44 | were not able to pick up the potentials because these action potentials produced by |
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44:50 | are only 1 to 2 milliseconds in . So you need it really fast |
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44:55 | in order to pick it up really equipment in order to display this on |
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44:58 | screen and then take a Polaroid shop then send it to a journal with |
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45:04 | description. Uh so now we realize what's really important and when we look |
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45:10 | these different subtypes of the cells, not only their anatomy that is |
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45:15 | it's not only where they're projecting or their locating in the network and whether |
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45:21 | excited or inhibitory cells. But it's very important the frequency and the pattern |
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45:28 | the action potential. So these are potentials here. Each one of these |
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45:32 | and you can see that the cell here on the left, produces a |
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45:38 | fast sequence of action potential. It's the exact same stimulus as the cell |
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45:44 | the right, but to sell on right response very differently to the same |
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45:51 | . And it never produces a very frequency of firing. So once we |
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45:56 | , not only doing, you individual cell action potential recordings, but |
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46:01 | capable of patching or recording from multiple neurons in the same area. We |
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46:10 | that these neurons speak the same language is action potential, electrical electrochemical |
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46:19 | But they all have slightly different And this is another distinguishing feature or |
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46:28 | different subtypes of south. So before get to the firing pattern of the |
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46:35 | potentials, we must return to this here and this slide uh may seem |
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46:48 | . This articles are posted in your supporting lecture documents. So if you |
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46:54 | to read the figure legend for this figure, you can It's somewhat dated |
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47:04 | back to 2008. But the principle where, what we're about to discuss |
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47:13 | the same. Let's start from talking what we're looking at is we're looking |
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47:20 | the campus just we're looking at one of this hippocampus. It's a small |
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47:30 | both sides of the brain. Hippocampus a hippopotamus but campus hippo campus mhm |
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47:45 | is responsible for semantic memories, facts, stories, interpretations, |
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47:59 | So in fact when you're talking about names of people and remembering short term |
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48:08 | memories, hippocampus is involved and hippocampus be affected by diseases like alzheimer's |
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48:18 | That's where you have a memory loss one of the symptoms of Alzheimer's disease |
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48:24 | the campus is also a part of we call the limbic system. So |
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48:30 | is not only involved in the memory and recall of that memory but it's |
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48:37 | involved in the emotional information processing and memories. As you know a lot |
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48:45 | crimes, memories are tied to a emotion and in fact the greater than |
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48:51 | sometimes the better is the memory or it is to forget. Ah So |
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49:02 | two are tied together. The campus also referred to as our key |
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49:11 | Are she core tax. Our key an abbreviation for archaic its ancient cortex |
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49:24 | the campus is ancient because it has three cellular layers on the top |
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49:33 | It has stratum Ready autumn straddle stance layer, bottom layer in the middle |
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49:40 | banned here. It has straddled from dollar Paranzino player and stratum. |
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49:48 | So it's three predominantly three layered structure that's what our key cortex because neocortex |
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49:58 | typically what you refer to cerebral Neocortex Is a six layer structure and |
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50:06 | stands for new. The neocortex is latest and the greatest in the human |
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50:14 | cognitive conscious and motor development skills and is three layered structure. So I |
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50:23 | hippocampus is trying to become a six neocortex slow and it will sell maybe |
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50:31 | some years. Who knows? So we were to take the hippocampus and |
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50:37 | were to ask a question. Other cells in hippocampus are the excitatory cells |
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50:44 | hippocampus. Uh So you were to a question what types of cells |
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50:54 | We talked about the two major Excitatory versus inhibitory cells. Right. |
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51:00 | we know that excitatory cells will express and inhibit their selves will express |
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51:07 | So you were sustained for glutamate, to 90 of the south and the |
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51:17 | are going to stain for glutamate which excitatory and the remainder 10 - 20% |
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51:26 | going to stay in for Gavin. you stand for these glutamate cells, |
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51:32 | want to ask the question, are different glutamate cells, how many different |
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51:38 | of cells, how many different subtypes excited for yourself. And so then |
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51:45 | will utilize dives, you will utilize like Golgi stain in particular because Golgi |
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51:53 | reveals the precise anatomy of the cell of that cell. So Golgi stain |
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51:59 | picked up by the cell, it reveal that it's so much located in |
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52:04 | layer and it turns out that the of all of these excited cells are |
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52:09 | densely populating this parameter way So out those 80, of all of the |
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52:16 | cells in the campus, most of 80 90% actually live in this pyramidal |
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52:24 | . There's so much live in But if you use the stand you |
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52:29 | see that there's a soma here from dollar layer. There's another phenomenal cell |
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52:34 | and orients layer and there's another one radiology. But then you look at |
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52:39 | morphology and you say there's nothing different their morphology. They have a pickle |
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52:45 | rides, they have basil done rides their projection cells So their axles are |
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52:50 | to come out of this network are to come out of this local |
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52:55 | One network from the parameter cells. it's going to project into other parts |
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53:00 | the brain. Okay. Because these excitatory projections for our little selves communicate |
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53:08 | between each other but also into the and sometimes far away neuron all networks |
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53:13 | which they connect to. So you that morphological and you say you know |
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53:19 | ? I can't really tell the The only difference I would say is |
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53:23 | it's the same looking karam. It'll except a very small number of them |
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53:29 | in the ready atom layer. That's living ready atom layer. A very |
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53:34 | number of parameters sell so much 20,000 . But I really if I do |
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53:41 | any other morphological description is the same of cells. And so I mentioned |
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53:47 | that different neurons and different cells in body and different subtypes of cells in |
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53:52 | body. Different subtypes of neurons in brain will express a slightly different subset |
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54:00 | genes, a slightly different variation. may have inter cellular markers that others |
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54:07 | have. And so these intracellular markers not just a marker. Oh the |
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54:12 | has something, they're typically meaning that have a different function. So some |
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54:19 | cells and most of them that live the valley layer will stay positive for |
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54:25 | which is called bending and Calvin them the calcium binding 30. So they |
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54:33 | a calcium binding protein in the But these don't, that means that |
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54:37 | going to buffer and regulate calcium functions the South using this Calvin gene protein |
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54:44 | a different way from these neurons. in fact these neurons will all speak |
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54:51 | same dialect, the same frequencies and of action potentials. So the only |
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54:57 | that we can really distinguish what turns to be two subtypes functionally in three |
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55:04 | that we look at the location of layers with Farrah Minal excitatory projection cells |
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55:10 | pretty boring. They have called indian they don't have called indian and it's |
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55:15 | just two or three subtypes of that morphological and distinguishable action potential pattern dialect |
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55:24 | indistinguishable. Very uh one distinguishing feature called in some cells express others, |
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55:33 | know and that makes them a different of the excited projections. So So |
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55:40 | next question to ask logically in this or in the study, what about |
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55:46 | Gabba neurons? These Gabba neurons comprise 10-20% of all of the cells in |
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55:54 | Hippocampus and in this area of the here. But are they all the |
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56:01 | subtype of inhibit third south. And , you would use the stains, |
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56:07 | try to reveal the location of the and the morphology. And when you |
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56:13 | near 1, 23 all the way 21. These are all different subtypes |
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56:22 | the inhibitory gaba cells that are local into neurons. That means that they |
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56:32 | communicate within this network here. But don't have little cells of the axles |
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56:38 | project into other areas into neurons do . And how come there's such a |
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56:45 | variety of these inhibitory cells and it out that if you say them, |
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56:51 | can very clearly tell the difference between of them the location of the So |
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56:56 | , you know, opera versus versus land then rights that are horizontal with |
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57:06 | growing vertically versus dendrite the stick lines are vertical and axles that are also |
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57:15 | vertically. So morphological li they're You already can sell the differences. |
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57:25 | what are some of the distinguishing factors . There's so much location. Then |
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57:31 | finally these yellow cups here. These cups indicate where these excited with these |
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57:38 | ourselves are going to target the So the cups are near pyramidal |
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57:45 | That means they're targeting parameters somewhere. the soldiers of these parameter cells and |
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57:52 | neurons that are located in the parameter in the south for example. Number |
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57:59 | . The cups, the yellow cups target the very ethical gender. So |
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58:06 | have very clear distinct morphology. The of the Selma's very distinct morphology in |
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58:15 | dendrites, lateral horizontal versus vertical and distinct projections on how they talking. |
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58:27 | they contact onto the parameter cells on apex, on the so hmas or |
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58:34 | . The soma is even on the . But what is the difference between |
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58:40 | number two and film and before morphological look identical to me. They have |
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58:50 | So Mazarin, the parameter layer number . Number four. The den drives |
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58:55 | vertically projecting. Number two. Number the axles or the synapses that their |
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59:02 | phenomenal cells are in the same region the abdominal cells. And the only |
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59:09 | that you would distinguish between these two of cells is both of them are |
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59:14 | called basket cells. And some of South. Number two is positive for |
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59:19 | specific cellular market called for monument. those are four is having another different |
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59:28 | markers such as C. C. . Which stands for calling. So |
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59:34 | they're actually two different subjects themselves. if you're submitting a paper and you |
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59:41 | performed any study to the cell. specific study let's say you're recording electro |
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59:50 | activity and you submitted your paper and said my cells are recorded from where |
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59:58 | cells in the hippocampus and the reviewers no thank you. Not for our |
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60:04 | . Send it someplace cells. Because it's too broad, it's too |
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60:10 | when you look at this very complex where the complexity actually stems from the |
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60:17 | and functional variety of the inhibitory If you look at this and simply |
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60:23 | I recorded from inhibitory cells, that's enough information. So in order to |
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60:32 | your reviewers that I recorded from number cell and from the parameter all |
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60:39 | What you have to do is you to prove them, you have to |
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60:44 | different frequencies of action potential. So have to show them these cells actually |
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60:49 | two different dialects. You have to the morphology and say you know what |
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60:55 | is the cell that's located and Orients and projected axons all the way to |
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61:02 | in this particular cell also has a sound marker in this case Samata statin |
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61:11 | it actually is some number 71 of favorite ones neuron that is called it |
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61:25 | from orients and it goes to all so this this is this is the |
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61:36 | that we recorded from but that's what takes to to specify what specific subtype |
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61:43 | neuron you're recording too. Especially if recording from inhibit ourselves. It's not |
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61:47 | big of a challenge if you're recording excited for ourselves because we have to |
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61:52 | stay for Calvin then and prove that cell you recorded from Calvin and positive |
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61:57 | not. You have to reveal the , the projections as self specific |
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62:03 | all of it. Yes. So more complicated than no. Uh very |
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62:15 | question. This circuit in the We're going to also look at the |
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62:21 | cortical circuits which are six layer circuits they're more complex too. This is |
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62:28 | what we call canonical, which means you will find these arrangements of local |
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62:36 | inter neurons that have a variety of subtypes targeting these excited projection sells locally |
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62:45 | are projecting excited during information. So from a computational perspective the complexity and |
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62:57 | if the brain comes from the variety the inhibit themselves and their ability to |
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63:03 | different dialects and express different molecules. fact, I wasn't maybe going to |
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63:09 | to the slide but maybe we can you were for example to target neocortex |
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63:17 | you were just to record from the of the neocortex here, let's say |
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63:21 | centimeter from different neurons you will soon out that these different neurons, they |
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63:27 | the same input. But this is output that they produce for the action |
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63:32 | . So this would be like bursting mm These are very fast firing cells |
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63:43 | earlier. Then you have that stuttering , this one is again continues but |
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63:58 | . This is delayed stuttering so it an input and it thinks about it |
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64:03 | 23 seconds and then it goes rubbing a bike. So these are different |
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64:13 | that the cells speak and these different stem from the inhibitor ourselves. So |
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64:22 | think more complex. I think definitely they're more difficult to understand it difficult |
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64:28 | identify a specific subtype of the But also we can process a variety |
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64:37 | different frequencies. Sensory we can have outputs in different frequencies because these inhibitory |
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64:46 | will locally control what the excitatory cells between the networks. So and this |
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64:58 | what we call the dialect of It's the same language, it's the |
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65:02 | action potential. But the pattern and frequency that the cells produce is the |
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|
65:07 | why they produce different frequencies is because express slightly different subset of genes and |
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65:15 | have different ion channels and therefore different biophysics that allow them to produce either |
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65:24 | , slower, delayed stuttering, continuous patterns of these action potentials. |
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65:31 | cause more damage to the laboratory self which one diamond which will cause us |
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65:45 | damage if you lose inhibit they're excited yourself. I think that I don't |
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65:53 | if you can put it on a . Kind of a two wave it |
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65:55 | you but it is more likely that neurological disorders associated with imbalance. Where |
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66:06 | less of excitation, there's lots of . Um And because if you look |
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66:19 | some of the significant networks, it's 10 to 20% of the self |
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|
66:25 | So if you lose 1 to 2% 80 to 90% it's not that much |
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|
66:32 | a loss of function or some But here You're looking at significant potentially |
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|
66:39 | decline in some balance in the brain between neurons. Uh Yeah, so |
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66:49 | need we need this variety, we these different types of cells to speak |
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66:55 | dialects because we have very complex sensory , bombarding us a different frequency, |
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67:00 | slow, some fast, some some continuous, we have to adapt |
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|
67:06 | them. Uh and we have to very complex information, writing motor |
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67:15 | playing games, speaking, painting, music, this is a motor |
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|
67:21 | And so you need again, if you can liken it to music if |
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67:26 | only have cells that can produce one of the action potentials. This rhythm |
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67:33 | none all that means all of the on the radio, you know? |
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67:41 | you can think about that in that as well. Alright, I think |
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|
67:45 | gonna end here today because after this gonna venture into a little bit more |
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67:52 | electrophysiology and then jump into glia. you have any questions about this hippocampal |
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|
67:59 | , hang on to them until I'll come back and review that slide |
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68:03 | . We can ask any questions, I'll point out some of the things |
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68:07 | may be important for you to know the exam from that slide. Thank |
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5999:59 | |
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