| 00:02 | This is lecture three of Neuroscience. we're going to finish talking a little |
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| 00:08 | about the history of neuroscience and the . But what you realized, I |
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| 00:14 | in the last couple of lectures is journey, this journey of inquisitive minds |
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| 00:20 | the ages, the millennia and trying understand the human anatomy and the human |
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| 00:27 | . There are limitations such that we cannot see uh the human brain. |
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| 00:38 | now we have this difficulty of having brain that's translucent. And so in |
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| 00:43 | to reveal the precise anatomy of the , we have to use the |
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| 00:47 | we highlighted two stains. OK. two stains were the Golgi stain and |
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| 00:54 | Nile stain. And we talked about fact that Golgi stain is really good |
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| 00:58 | reviewing precise anatomy and morphology of these as only a fraction of the neurons |
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| 01:05 | up the stain in bulgy stain, of the neurons. And we are |
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| 01:10 | to pick up the stain, but stain is going to expose the sous |
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| 01:14 | these cells. So you don't get anatomy and morphology of the processes, |
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| 01:18 | dendrites and Toons in that. Uh missile stain is really good for the |
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| 01:25 | detect methods uh uh were invented essentially Doctor Kin and Brodman. And there |
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| 01:30 | methods to essentially describe the precise anatomy structure of the cellular units of neurons |
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| 01:39 | glia. Of course, in the , the stacking directions densities and so |
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| 01:45 | . So with light microscope, we pretty good resolution. But if you |
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| 01:50 | , we need electron microscope in order visualize synopsis. The reason why is |
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| 01:57 | are only about 20 nanometers in And the light microscope resolves up to |
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| 02:03 | micro meters which is 100 nanometers So it's not powerful enough to visualize |
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| 02:10 | synopsis. OK. Now you have microscope can help you visualize the |
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| 02:18 | Uh but we also don't need to the stage to visualize neurons. So |
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| 02:24 | slide was an example where we can infrared microscopy, infrared imaging in order |
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| 02:30 | visualize neurons especially on the surface of brain or the surface of the slices |
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| 02:34 | are placed under the microscope. So no stain that is being used |
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| 02:39 | And these techniques allow us to visualize and place microelectrode on these neurons so |
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| 02:45 | we can record electrical activity from these cells. This technique is called electrophysiology |
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| 02:52 | neurophysiology. So you don't need a there. Now, if you uh |
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| 02:57 | electro microscopy, what you can do you can zoom in and you will |
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| 03:02 | that there are these synapses. So the presynaptic side. The presynaptic side |
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| 03:08 | the side that is responsible for release the neurotransmitters. And essentially the presynaptic |
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| 03:18 | here are these external terminals that are with, filled with vesicles that have |
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| 03:24 | in them. This is presynaptic. will release neurotransmitter and dendritic spines are |
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| 03:31 | . They're going to be receiving that and responding to that signal on the |
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| 03:37 | spines. So this is something that quite interesting that we discussed that's unique |
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| 03:43 | neurons. And the sense that you see it even further today is that |
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| 03:48 | have for the most part, the morphology as a lot of different cells |
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| 03:53 | or similar to other cells in the . It actually has the same organ |
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| 03:58 | in all types that other cells have we'll discuss, but it has these |
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| 04:03 | . And so remember Ramonica Hall says dendrites is where information comes in where |
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| 04:09 | gets received essentially. And what you is you have these optical dendrites, |
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| 04:15 | called ical that they're called ICAL because typically referred to dendrites that are coming |
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| 04:24 | the apex of the pyramid. So lot of times this is a petal |
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| 04:32 | . This is one of the major neurons in the brain. It's the |
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| 04:37 | excitatory neuron in the brain, it an apex. Therefore, these dendrites |
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| 04:44 | referred to as optical and it also the base. So the pyramid has |
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| 04:50 | base. This is the nucleus of neuron. This is the base and |
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| 04:55 | dendrites are basal dendrites and it will an axon that comes out, an |
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| 05:03 | will have its axonal terminal that will the neurotransmitter vesicles in here. And |
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| 05:11 | also learn that these axons and neurons myelinated. So they're insulated for a |
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| 05:19 | . Right. We'll talk about that . But the interesting thing are these |
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| 05:24 | , these little protrusions that we call and because they're on dendrites, these |
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| 05:31 | are referred to as dendritic spines. there are only about one micrometer in |
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| 05:38 | . And during the early development and the adulthood too, you have a |
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| 05:44 | number of spines that are formed in spines and those protrusions, they're |
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| 05:50 | So they can become larger and they can become smaller in size, |
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| 05:55 | and weaker, they can be So some of these spines will disappear |
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| 06:00 | new spines can be formed. So is a plastic process and this is |
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| 06:06 | lot of learning and memory in which is on a cellular level is |
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| 06:11 | here and on a broader level, you think about learning and memories, |
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| 06:16 | you're learning something and memorizing something, neurons have to do that so that |
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| 06:21 | have a memory. And so these the places of contact. Most of |
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| 06:26 | synapses will be formed along the dendritic and the dendritic spines and they're one |
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| 06:32 | in diameter. So they're really small and they're really malleable and plastic |
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| 06:43 | And what we have in modern experimental , I think I already uh talked |
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| 06:49 | this is the ability to visualize single , single dendritic spines, which is |
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| 06:56 | synapse, single cell connectivity of these into networks, activity morphology and activity |
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| 07:05 | these neurons. And in a clinical , we're gonna use positron emission tomography |
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| 07:11 | non invasive imaging technique to look at brain maps. So I already mentioned |
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| 07:16 | that these hotspots we refer to as maps and they are spreading. If |
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| 07:21 | spreading, they're also referred to as waves. And I mentioned that in |
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| 07:26 | clinical setting, these are great noninvasive tools to measure activity in the |
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| 07:32 | . We're not looking at morphology, looking at activity of the brain, |
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| 07:35 | it's metabolic activity, so indirect neuronal through metabolism, through consumption of oxygen |
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| 07:44 | glucose. Uh However, the limitation is the resolution. So ultimately, |
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| 07:51 | want the clinical setting to be able see overall activity of the brain and |
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| 07:56 | in and see individual neuronal circuits, and maybe even synopsis that could be |
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| 08:03 | uh potentially causing some early pathology. it's a, it's a, it's |
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| 08:08 | dream, but I think it's a that will turn into reality in this |
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| 08:13 | , virtual reality and artificial reality. talked about the fact that a person's |
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| 08:20 | maps, therefore, physiology of the . Therefore, this physiology of these |
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| 08:26 | are reflective of what you are what you are thinking what you are |
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| 08:33 | , right? These are the brain . So if you're looking at the |
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| 08:40 | , it's the occipital lobe that lights , you're talking, speaking, it's |
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| 08:46 | uh uh Broca area on the motor that light up. So these are |
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| 08:55 | maps. These are your thoughts, are your feelings, these are your |
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| 09:00 | , these are your mother commands that gonna come out of his brain. |
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| 09:04 | it could be as simple as playing game and clicking a mouse and you |
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| 09:08 | a certain image or certain map of brain activity and that map of the |
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| 09:13 | activity, the locations, the activation different neural networks changes in the presence |
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| 09:20 | virtual reality. And it's not an to say, oh, so does |
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| 09:25 | mean it becomes smaller and more That's just an illustration to show that |
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| 09:29 | is a significant difference in brain maps two dimensional spaces versus the virtual reality |
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| 09:38 | reality uh applications. So this is of the brain. And there are |
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| 09:47 | different levels of which we understand and neuroscience, molecular cellular systems, behavioral |
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| 09:54 | , computational neuroscience and neuroscience careers. , a lot of these careers |
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| 10:02 | for example, neuroscientists is a phd anatomist, PhD neurobiologist. You have |
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| 10:08 | neurosurgeon neurological surgeon is an MD. think I mentioned the residency for neurosurgery |
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| 10:14 | 10 years after you get an Uh it's really rigorous neurologist is an |
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| 10:21 | . It's a person that doesn't cut brain. So the surgeon is the |
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| 10:24 | that cuts your brain. The neurologist the one that consults you diagnose you |
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| 10:28 | treats a nervous disease of some Neuropathologist can be MD or phd. |
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| 10:35 | there are many talented phd S that in the hospitals, running the uh |
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| 10:41 | labs, uh uh forensics, pathology so on. Uh neuropharmacology. We |
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| 10:48 | learn quite a bit about different We will learn about interactions of neurotransmitters |
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| 10:54 | these receptors, but also how drugs medications interact with those different receptors. |
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| 11:01 | medications, as well as some uh substances. Uh Psychiatrist is an MD |
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| 11:11 | nurse electric neurodiagnostic technician. That's pretty , right? So there's a lot |
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| 11:17 | different applications for Neuroscience. There's a big field of rehabilitation of ner ner |
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| 11:23 | nervous rehabilitation nerve habilitation. But for example, when COVID came about |
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| 11:30 | a lot of people lost a sense smell. Most of us were |
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| 11:34 | And a few days later or a later, that sense of smell or |
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| 11:38 | returned for some people and not a small fraction. It became a chronic |
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| 11:45 | . Uh they have potentially lost certain of smells, although the smell sense |
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| 11:52 | smell returned, but they cannot smell . And so there's in reaction to |
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| 11:58 | , there's actually like kind of a all factory rehabilitation center. I think |
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| 12:03 | is uh somewhere near woodlands. It developed for that how to retrain your |
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| 12:09 | and your brain to be able to smells, again, different types of |
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| 12:18 | . So it's all changing with the world is many different applications of |
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| 12:28 | And I use this link because uh Doctor Kilar updates these different um applications |
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| 12:37 | future careers that somebody with neuroscience can . And the final two slides, |
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| 12:43 | one before the final slide is a of neurological disorders. So I want |
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| 12:47 | to know this in order to answer questions, simple definitions on your liter |
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| 12:54 | lung. We will talk to a extent about Alzheimer's disease and epilepsy. |
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| 13:00 | example, multiple sclerosis, we will talk about spinal paralysis. We will |
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| 13:06 | talk about schizophrenia in this course. from maybe I mentioned cerebral palsy, |
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| 13:12 | will not talk about. So I want you to know all of these |
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| 13:18 | neurological disorders. And throughout the you will know a lot more |
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| 13:22 | for example, epilepsy or Alzheimer's But for now, I want you |
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| 13:27 | know these definitions so you can orient . You're in neuroscience course. Somebody |
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| 13:31 | you, oh, it's Parkinson's You should know what Parkinson's disease is |
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| 13:36 | you should know it now and you know it way better at the end |
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| 13:39 | this course. OK. We'll touch stroke when we talk about COVID-19 |
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| 13:47 | Um as it's one of the consequences infections by this virus in the brain |
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| 13:52 | can lead to um thrombus formations in blood vessels and stroke, rupture of |
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| 13:57 | blood vessels. Goal of neuroscience is learn how the nervous system functions, |
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| 14:03 | not really just to know how it . If we want to apply our |
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| 14:09 | , um we want to understand the and we want to correlate how one |
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| 14:16 | with the activity in the brain, these maps that I was talking |
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| 14:19 | Can we predict, for example, maps an individual may form? Can |
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| 14:23 | predict their behavior? Um Computer assisted techniques are gonna be very valuable. |
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| 14:30 | that's where A I comes into You know that about 25 to 30% |
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| 14:35 | all of the pathological test results that into MD Anderson Cancer Center are |
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| 14:42 | But they're different from what MD Anderson pathologist would tell for that same |
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| 14:49 | They would maybe identify different diagnoses. a lot, that's 20 25%. |
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| 14:57 | one in four. So if you a diagnosis for cancer, there's one |
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| 15:03 | four chance that that pathology, just pathology diagnosis. I'm not talking about |
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| 15:09 | the other tests that may follow So typically, if you have some |
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| 15:12 | or something, it will get cut , we will take a sample of |
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| 15:18 | , right. So, but this now you look at the sample of |
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| 15:24 | tissue and there's a 25% chance that gonna tell a person the wrong diagnosis |
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| 15:32 | ? Because there's a human element It doesn't matter that there is automation |
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| 15:37 | there is staining for certain markers and . In the end, it is |
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| 15:42 | person that is going to interpret that . The same as your brain scans |
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| 15:50 | ray scans radiologists, right? You take an X ray and then they |
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| 15:53 | , oh, radiologist has to look it and then send you the |
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| 15:57 | So it's not the machine that spits the report and says you have a |
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| 16:01 | bone, but it's the radiologist that the files in front of the computer |
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| 16:07 | 10:38 p.m. Tired, maybe and maybe tired, maybe at 6 a.m. any |
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| 16:16 | , right? But there is a element there and the the human bias |
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| 16:20 | how one looks at the picture and it in another person. Another algorithm |
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| 16:26 | fact may interpret the same result And this is where artificial intelligence, |
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| 16:32 | think in computer assisted uh methodologies and models can really be useful to |
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| 16:40 | out that human bias and have uh precise, more spatially precise, uh |
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| 16:49 | diagnostically precise suggestions because an individual is a library, they have read books |
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| 16:58 | the library. But what A I do is they can read the whole |
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| 17:04 | and that's the difference. And you know things a little differently if you |
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| 17:08 | access and more experiences. And that's happens with life. People get more |
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| 17:12 | , they've seen more things they can this is like this this is like |
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| 17:15 | , this is small like that. non invasive methods and new treatments for |
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| 17:20 | nervous system disorders. That's where where we want to understanding of the |
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| 17:25 | is great. We're not, you , Elon Musk is looking to create |
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| 17:29 | neuralink robot, a device that will somebody's thoughts that will hook into the |
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| 17:36 | , right? When avatar, you when uh uh what is the name |
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| 17:42 | the movie where they have the avatars around? Come on. It's at |
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| 17:52 | tip of my tongue. Wow. . So I was so excited when |
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| 18:04 | , well, you know, when went with their big chaos to the |
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| 18:07 | of life and connected to that tree life because I thought like, |
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| 18:11 | that's gonna be the story, you , collective consciousness, thought process and |
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| 18:18 | , peace, love, you 20 minutes later as, you |
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| 18:23 | the same old Hollywood formula, shoot up, you know. But so |
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| 18:31 | sort of like where Elon Musk wants go. He wants to, you |
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| 18:35 | , look into your brains and read thoughts and there's plenty of volunteers uh |
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| 18:41 | want to work with him. I over 2000 that have signed up |
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| 18:46 | for this experimental and plantation. all right, this concludes our introduction |
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| 18:56 | neuroscience and where the future of it go. It's really, we don't |
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| 19:03 | , but we hope it's going to uh a lot of people with neurological |
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| 19:07 | in particular. Mhm. All And now we're moving into neurons and |
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| 19:25 | and with neurons and glia, we about 10% of all the cells in |
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| 19:30 | brain, the neurons, 90% are . So I say that neurons are |
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| 19:35 | chips in the chocolate chip cookie and cookie is boring without chocolate chips, |
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| 19:42 | ? Wants just the cookie without chocolate . You want something in it. |
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| 19:47 | that's the neurons. But leah which the dough, you can't have a |
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| 19:52 | without a dough, you can't have brain without bleeding. And that's how |
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| 19:58 | it is not just in supportive functions also in the development of the brain |
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| 20:04 | homeostasis of the brain and normal functioning the brain. In order to visualize |
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| 20:09 | , we have to exercise the gain the brain is mainly the stain or |
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| 20:15 | infrared microscopy. And these different stains allow you to visualize neurons differently. |
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| 20:21 | all of the processes and the fraction them miss all of the neurons and |
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| 20:26 | of their Somas and there's a slew other stains and we'll talk about some |
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| 20:31 | them in tracers uh later today. we already heard about the reticular theory |
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| 20:38 | the neuron doctrine. Remember that og not that go you said was a |
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| 20:43 | of the reticular theory that the brain one continuous cytoplasm, one cum with |
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| 20:51 | plasma membrane surrounding this whole clump. uh Santiago Ramon Cajal was a proponent |
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| 20:59 | neuron doctrine that these neurons are discrete units. That the connections between these |
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| 21:06 | are plastic. That there is a principle of polarization poles where information comes |
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| 21:15 | the cells here in the dendrites gets in the SOMA and gets sent out |
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| 21:20 | these dark processes, dark stain processes . The prototypical neuron has a lot |
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| 21:29 | features of a regular cell or of course mitochondria via para is |
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| 21:36 | rough on the plasma reticulum, polar . But it also has these unique |
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| 21:43 | spons that we talked about. And also has an axon that has myelin |
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| 21:50 | wro wrapped around it for insulation. axon hillock is where the action potential |
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| 22:00 | going to be generated. So this where the action potential gets generated in |
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| 22:06 | axon hill up and then then it regenerated in each node of run veer |
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| 22:12 | it reaches the external terminal. And has the same amplitude at the external |
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| 22:19 | as it started here at the axon segment. OK. Uh Doctor. |
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| 22:26 | . So with more nodes of you said is there increased propagation of |
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| 22:31 | signal? It's not necessarily more nodes increase the propagation. Uh The number |
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| 22:38 | nodes will depend on the length of Axion. Some axons are short and |
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| 22:42 | may just have a few nodes, will have longer axons. But you |
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| 22:47 | learn when we study action potential is unique composition of the channels of the |
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| 22:51 | of run beer that allow for this potential to get reproduced at each node |
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| 22:56 | run beer. And, and the for this, uh what we call |
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| 23:04 | propagation or regenerative propagation is to preserve amplitude of the action potential from the |
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| 23:12 | Axon here, Axon Hill walk to very terminal end of its axon. |
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| 23:21 | happen the same way genes they get transcribed um into rnarnas, get |
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| 23:33 | OK. Uh And you have slicing top. So you have RN |
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| 23:40 | it gets spliced into messenger RN And we're to a certain extent uh |
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| 23:46 | variants of uh of one another slightly variations of what happens during the |
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| 23:54 | But you can also have a pathological variant. So this process is not |
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| 23:59 | tightly regulated, you can have a MRN A splice variant that is going |
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| 24:05 | be translated into a faulty podium. example. Now we live in the |
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| 24:16 | genomic era and in this post genomic , we know what genes, what |
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| 24:24 | we have, what they code what their sequences are. And we |
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| 24:31 | a lot of genetic methodology in neuroscience in modern day biology too, so |
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| 24:39 | can manipulate the genes in the experimental , we can knock out genes. |
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| 24:46 | to knock out mice as the gene been deleted or knocked out. So |
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| 24:51 | pick one of the genes from, say 30,000 in the brain and you |
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| 24:56 | I'm gonna target and knock out a and you erase that gene. |
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| 25:00 | you want to see what the consequences . If you erase that gene, |
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| 25:04 | would you do that? Well, you, for example, found |
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| 25:09 | a person who has epilepsy and you that they have a genetic mutation and |
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| 25:16 | particular gene is affected by a genetic . And that symptomology or the disease's |
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| 25:23 | . And you want to understand the of this disease. You want to |
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| 25:27 | how this this epilepsy come about from mutation. Therefore, you're going to |
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| 25:32 | that mutation. So you're going to potentially with either lower species organs lower |
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| 25:38 | rodents or rodents. And in now you will try to manipulate that |
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| 25:44 | . One of the ways that you manipulate is what if I take that |
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| 25:47 | out? Am I going to recreate this animal? The same condition that |
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| 25:53 | just observed in human that has that , let's say the mutation causes seizures |
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| 25:59 | epilepsy. And I have a a knockout mouse and this mouse is |
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| 26:04 | also that has epilepsy. Then it's successful model, it replicates at least |
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| 26:09 | of the symptomology. Now, we to make sure it replicates as much |
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| 26:15 | the human condition as we can replicate on the knowledge that we have. |
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| 26:20 | , that's epilepsy is a disease that study in greater detail, but there |
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| 26:28 | many different causes of epilepsy. One them is genetic, but there are |
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| 26:32 | causes of epilepsy that are environmental, traumatic brain injury, glioblastoma, cancerous |
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| 26:41 | in the brain. And as gauge epilepsy following traumatic brain injury. So |
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| 26:49 | not always a genetic component. But it is a genetic component, then |
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| 26:53 | wanna go and manipulate the genes. epilepsy formed due to traumatic brain |
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| 26:59 | what are you going to do with ? No, you answer my |
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| 27:11 | Oh, you're not listening to I said I know you because you |
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| 27:14 | the next question. So you have genetic mutation and it has epilepsy. |
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| 27:18 | I'm gonna try to tinker with that in the animal. I have traumatic |
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| 27:24 | injury and I developed epilepsy. What my model going to do? |
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| 27:31 | Not just traumatic brain injury, you to replicate. So if the cause |
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| 27:38 | the gene, you want to manipulate gene, if the cause is a |
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| 27:43 | , you want to induce the same using the chem. If the cause |
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| 27:47 | traumatic brain injury, we want to the same condition using trat brain. |
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| 27:52 | that make sense? But then the didn't have any kind of energy. |
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| 27:56 | started out don't know where he supposed be stressed or something. It's called |
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| 28:01 | . So what is stress? What stress cause? Maybe inflammation mo maybe |
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| 28:06 | expression of cortisol. Therefore, what your model going to be a stress |
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| 28:11 | of inducing too much cortisol, stressing animal out? Seeing if you can |
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| 28:16 | the condition, right. That will the model then. So yeah, |
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| 28:20 | many different models. There's many different of diseases come come about them, |
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| 28:25 | in epilepsy that it can be what call sporadic mutation. It can be |
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| 28:32 | chemical exposure can be exposure to nerve could be traumatic brain injury. And |
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| 28:38 | each case, you're gonna try to that as a model in order to |
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| 28:43 | as close as possible to the human . What does it look like when |
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| 28:47 | replicate a traumatic brain injury in a or something? Well, we're going |
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| 28:54 | a tangent here a little bit. uh, what does it look |
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| 28:58 | You know, it's a good So there are many different types of |
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| 29:03 | brain injuries. A whiplash is a brain injury. So you, you |
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| 29:11 | hit, your car gets hit really . You have a massive whiplash, |
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| 29:15 | have a headache, you have neck , traumatic brain injury, you repeat |
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| 29:20 | enough times you could end up dead . Ok. So, so what |
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| 29:28 | be a replica of the whiplash? sort of a water water repercussion, |
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| 29:35 | sort of a movement of a cage which a mouse is to replicate |
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| 29:41 | Right? Ok. What about the brain injury where you had a piece |
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| 29:46 | shrapnel that penetrated into your brain? not a whiplash. How are you |
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| 29:50 | to model that? You're actually gonna a little computer controlled hammer and you're |
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| 29:56 | , and you're gonna, and you're , essentially, it's called controlled cortical |
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| 30:02 | in a controlled manner. You exactly the impact, the strength of |
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| 30:05 | impact, the duration of that So, it's a model is, |
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| 30:11 | that what's happened in humans? You , they just get clocked with a |
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| 30:15 | , clock with a hammer in the , in the same position all is |
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| 30:19 | . But that's the best that we do. So, good questions. |
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| 30:24 | the inquisitive minds going now. genetic manipulation, we're gonna genetically mutate |
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| 30:31 | , the the knock out the we can also knock in a gene |
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| 30:34 | is native gene is replaced with a gene. So you're not eliminating the |
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| 30:39 | , but now you have tinkered with gene, you have some different uh |
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| 30:45 | gene that you replace with a, a normal gene transgene as genes are |
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| 30:50 | in over express. So you can introduce an over expressive gene. And |
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| 30:57 | lot of these are models for neurological , many of which we have, |
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| 31:02 | will have genetic basis, but many diseases will not have a genetic |
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| 31:08 | They will have traumatic uh chemical um basis, stress driven or whatnot. |
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| 31:22 | let's say you have two brains, , one is the normal brain and |
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| 31:25 | two is an epileptic brain. And are called the gene micro arrays. |
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| 31:31 | we're really good, we can have , these are micro arrays or micro |
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| 31:37 | . These plates will have these little of them and they can have as |
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| 31:41 | walls as you order the microplate you can have 5000 walls, 10,000 |
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| 31:47 | , 30,000 watts. Each one of walls will have a spot of synthetic |
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| 31:52 | DNA with gene specific sequence because we it post no era synthesize that and |
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| 32:00 | put place it in each well. . So we have 30 different unique |
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| 32:05 | DNA sequences that we placed within Well, each one of these sequences |
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| 32:12 | for a different gene. So you'll 30,000 wells, you'll have 30,000 synthetic |
|
| 32:19 | sequences. OK? You place it this wall and it's sort of like |
|
| 32:24 | , a Velcro by using the knowledge a Velcro because Velcro has two pieces |
|
| 32:28 | have to stick together the hard piece the soft piece. So here's |
|
| 32:33 | the, the one side of the who is landing there? Your question |
|
| 32:38 | I want to know what genes have , what genes are different in expression |
|
| 32:46 | normal brain versus the epileptic one. you can take the brain matter homogenize |
|
| 32:55 | . You can apply it into 30,000 . Usually it's automated applications of homogenized |
|
| 33:03 | , right? This is the other of the Velcro. Now, genes |
|
| 33:08 | will have equivalent expression in both brains this is red vile and this is |
|
| 33:13 | green vial that will mix to the proportion. We'll get a yellow column |
|
| 33:19 | those genes, all of the wells will have yellow signal. And this |
|
| 33:24 | fluorescent markers typically that are placed on wall too. So all the ones |
|
| 33:29 | have yellow signal, the genes have changed. There's no difference between normal |
|
| 33:33 | genes and epileptic brain genes for those subset of hundreds of thousands of |
|
| 33:40 | Now, genes that will have red reduced expression in gray two genes that |
|
| 33:46 | have green signal here are reduced expression gray one. So now you can |
|
| 33:55 | what genes changed and it's not only . In fact, this technique is |
|
| 33:59 | little bit more sophisticated. You can also which genes have been upregulated and |
|
| 34:03 | genes have been down regulated a normal versus hyla brain. But what happens |
|
| 34:09 | you have this 30,000 wells? What the result you're expecting that only one |
|
| 34:14 | is going to change? No. the most likely scenario is that you're |
|
| 34:19 | see hundreds of genes that are different normal brain and epileptic brain, hundreds |
|
| 34:25 | them that are different, some that upregulated, some that are with a |
|
| 34:31 | expression. Mhm. Is this There's 500 genes that are different between |
|
| 34:40 | brains and normal brains. Well, is because it's not 30,000. So |
|
| 34:45 | already narrowed it down to 500. what are you gonna look for |
|
| 34:50 | Maybe out of those 500 you're gonna for the 10 that are most over |
|
| 34:55 | 10 that are most under expressed in brands, right? And you |
|
| 35:03 | yeah, why, why are these important? Because there's the biggest change |
|
| 35:08 | . But then you're gonna do some things, right? You're gonna go |
|
| 35:11 | your mentor and say, I see genes have regulated, I'm interested in |
|
| 35:15 | top 10 and bottom 10 down And then your mentor like Cilia Golgi |
|
| 35:21 | , I only believe these two genes involved. Therefore, you're gonna spend |
|
| 35:24 | rest of your phd four years studying two genes, go lock yourself up |
|
| 35:28 | the lab, talk to me every of weeks or so. So |
|
| 35:34 | and that's it. You're stuck with two genes. So if you are |
|
| 35:38 | Santiago Ramon Cajal, maybe after you pick up the third gene that |
|
| 35:45 | do additional studies on because maybe what do is you, you know, |
|
| 35:49 | mentor, of course, has a of knowledge also has a better understanding |
|
| 35:56 | you do. But a lot of things are driven by grant funding and |
|
| 36:02 | are issued to fund certain things, everything. So if you get the |
|
| 36:06 | , it's not like you have freedom do absolutely everything in any animal |
|
| 36:10 | It's like, no, you have animal studies and these animal models, |
|
| 36:13 | have to get approvals. It's not it's very difficult to have approvals for |
|
| 36:20 | manipulations for pharmacological treatments and the higher the species, the more of the |
|
| 36:28 | tape, the more of the regulation have, the more of the ethics |
|
| 36:31 | have associated with those studies. But , you know, you're as a |
|
| 36:36 | person, gonna say, my mentor to study these two genes. He |
|
| 36:39 | got a grant to study these two . Um, but I'm, uh |
|
| 36:45 | very inquisitive individual. I'm gonna go the library, I'm gonna read about |
|
| 36:49 | 10 genes and I'm gonna find out two others have just been shown like |
|
| 36:55 | year, the last two months, just emerged. These two genes are |
|
| 37:00 | important for our policy and run down my mentor and say, hey, |
|
| 37:05 | you seen these? He's like, is this? What journal does it |
|
| 37:09 | from? Is it really a good ? And then it will say, |
|
| 37:14 | , well, I didn't know it's human factor again. So your |
|
| 37:17 | it's what your mentor have read, hasn't read the literature for the last |
|
| 37:21 | months. And that's ok because it doing something else, multiple projects |
|
| 37:26 | but you can bring that up to . You can be an inquisitive |
|
| 37:29 | In other words, there's also comparisons the literature to help you identify those |
|
| 37:35 | genes to help you further your Once you have a good bird's eye |
|
| 37:40 | on the changes, massive changes and number of genes, you can now |
|
| 37:48 | in on something that is based on findings, previous literature or you |
|
| 37:53 | mentors uh Neil had a question. So for, for something like |
|
| 38:00 | if it has different causes that um could be like a high or you |
|
| 38:08 | pass down. But is it possible the 500 different between those two? |
|
| 38:15 | , that, of course, And uh don't get stuck in the |
|
| 38:21 | number. This is just a, is just an example. But |
|
| 38:26 | it's a great question. So two brains and especially if we know that |
|
| 38:31 | , it causes the very different one let's say the genetic uh mutation and |
|
| 38:37 | comparative potential. Another one is an to a chemical or something like |
|
| 38:43 | There will be differences between two of . And in fact, a lot |
|
| 38:48 | times epilepsy is also referred as So it's almost like a number of |
|
| 38:55 | diseases that fall under the same Typically with repeated seizures is one of |
|
| 39:00 | main symptoms for diagnosis. But it's like different types of diseases because |
|
| 39:07 | they cause the cause is a different . Somewhat similar. The expression of |
|
| 39:13 | seizure could be similar. But also are many different types of seizures that |
|
| 39:19 | also study. Yeah. All Moving on boons are made, uh |
|
| 39:30 | of them remain in the cytoplasm, that get processed through rough endoplasmic |
|
| 39:35 | they remain or become membrane associated And we'll study most of the membrane |
|
| 39:41 | proteins, receptor channels, transmembrane G protein to receptors are all membrane |
|
| 39:47 | for our course purposes. That's going be our major focus. This guy |
|
| 39:53 | familiar. Yeah, you did that . So the Golgi apparatus. So |
|
| 40:03 | you're staining things, as you're studying , you, you discover things and |
|
| 40:08 | you discover things, you can put name to it. So Golgi |
|
| 40:12 | goi stain, he wanted the whole to be gold like everything. Smooth |
|
| 40:17 | reticulum. So uh you have the on the plastic reticulum, you have |
|
| 40:24 | sorting to their final destinations and adjustments happens by Golgi apparatus. Now, |
|
| 40:32 | is very important. Mitochondria is the of energy in the body and the |
|
| 40:38 | produces adenosine triphosphate. A TP. uses dietary stored energy sources, protein |
|
| 40:44 | sugar fat. It becomes pubic acid . It generates a TP with oxy |
|
| 40:52 | , generates a TP and out gasses dioxide. They have this crep cycle |
|
| 40:58 | cellular respiration going on in mitochondria. this is really important for the brain |
|
| 41:05 | think about this, your brain is £3.5 and wait. And that doesn't |
|
| 41:15 | much between a person that weighs 100 £50 and £350. Uh There's not |
|
| 41:23 | be a double in the weight of brain. It's gonna be around |
|
| 41:28 | How much of that is your total body mass, let's say £200 |
|
| 41:37 | How much of that is your 1.51 0.752% let's say of the total |
|
| 41:45 | mass is your brain, but it 20% of the total energy. So |
|
| 41:54 | , in the mathematical physics terms, say it's a system that has been |
|
| 41:59 | outside of its equilibrium. It's consuming more energy for the size that it |
|
| 42:06 | . But we need constantly renewed sources energy and a TP for neurons to |
|
| 42:12 | normally. So this £3.5 mass sucks of all of the dieters stored energy |
|
| 42:19 | that essentially get transformed into a And used by the brain phospholipid |
|
| 42:28 | We refer to phospholipid bilayer as a fluid mosaic model. And we refer |
|
| 42:35 | it as fluid mosaic model because these they form by having the polar hydrophilic |
|
| 42:44 | groups that face either the extracellular reus or the cytoplasm inside the cells. |
|
| 42:51 | the fatty acid chains right here, acid chains are hydrophobic. So the |
|
| 42:57 | acid chains will come in meet each forming this bilayer. Even that you |
|
| 43:04 | cholesterol, you have transmembrane proteins that channels that allow for the passage of |
|
| 43:09 | and small molecules. You have g coupled receptors that are proteins that are |
|
| 43:15 | to the membrane associated protein complexes that stimulate secondary messengers and turn on downstream |
|
| 43:24 | cascades. It's coated with carbohydrates. a very dynamic fluid is structure. |
|
| 43:31 | these elements move through the membrane and nervous system, they move fairly |
|
| 43:37 | they can move through the entire neuron the matter of milliseconds. Some of |
|
| 43:41 | proteins within the plasma membrane and the boundaries in the shape of the |
|
| 43:48 | And the membrane is supported by the cytoskeleton. Uh elements that we'll discuss |
|
| 43:54 | the following slide. Um If you on this and some of the other |
|
| 44:01 | that I have. How was this ? So you can watch it on |
|
| 44:10 | own. And I will have links this in my slides that will link |
|
| 44:15 | to either videos and sometimes they'll link to articles too. And um you |
|
| 44:21 | find it all there. The major subtypes of cyto skeletal elements that we |
|
| 44:25 | is tubulin molecules that form microtubules are largest elements, 20 nanometers in |
|
| 44:33 | Then we have neurofilament and then we microfilament which are the smallest cyto skeletal |
|
| 44:40 | and they're made up of the smallest molecules. So if you look there |
|
| 44:45 | a whole kind of a structure, a lattice like structure, almost a |
|
| 44:52 | like structure of larger molecules, microtubules intertwined with micro filaments and neuro |
|
| 45:01 | This is a cross section of an . So an axon has been cut |
|
| 45:07 | , remember, the axons are So we cut through the axon here |
|
| 45:12 | the middle on the outside, we're myelination. So these are the sheets |
|
| 45:17 | myelin that wrap around the axons and the axon, you're seeing these spaghetti |
|
| 45:25 | uh structures and those are microtubules. these are referred to as microtubule highways |
|
| 45:32 | it will be very prominent, especially the axons because the cell makes a |
|
| 45:38 | of things in the SOMA and it to transport things from the into the |
|
| 45:43 | aspects of the cell. And it needs to take things back from the |
|
| 45:48 | aspects of the cell, the distal back into the SOMA for reprocessing or |
|
| 45:56 | or re synthesis. So if we at this image in blue, you |
|
| 46:03 | acting molecules. And what happens is these cyto skeletal elements, they can |
|
| 46:12 | and form longer chains. They can up and depolymerize into shorter chains. |
|
| 46:21 | allows you to have all sorts of in different directions to support the structure |
|
| 46:28 | smaller uh chains that are more easily down and they can float into a |
|
| 46:37 | direction and join with another structure or the microtubules around the microtubules. So |
|
| 46:45 | have this going on and where Acton in blue. And you can see |
|
| 46:50 | the smallest elements, they are supporting outer boundaries and outer edges of the |
|
| 46:55 | membrane. So when I said that genetic spines are malleable, they change |
|
| 47:01 | shape. That means the cyto skeletal underneath the plasma membrane, they also |
|
| 47:08 | to rearrange and change their lattices, polymerization depolarization elements in order to change |
|
| 47:19 | overall shape of the plasma membrane. , these are not static elements. |
|
| 47:26 | they they're changing elements because the shape shape may be the same but the |
|
| 47:32 | boundaries of that cell shape will But what is shown here in yellow |
|
| 47:38 | tubulin. And you can see that of tubular and most of microtubules are |
|
| 47:43 | the selma. And then you see very clear tubular micro tullar highways going |
|
| 47:50 | the processes also. Yeah, I . Are you still strange or is |
|
| 47:56 | are you still sharing your screen Am I sharing it? Oh, |
|
| 48:01 | mean on the zoom? Oh, a good question. No, I'm |
|
| 48:13 | . Yeah, it's better if I . Ok. So the cyto skeletal |
|
| 48:18 | , everything that I talked about the two minutes is in its slides. |
|
| 48:27 | that's the advantage of being in Now you can see that some of |
|
| 48:32 | micro jugular highways that will have their proteins such as Ken and these motor |
|
| 48:38 | will transport, for example, vesicles the SOMA into the distal aspects. |
|
| 48:45 | going to be another motor protein divan will be moving in the opposite direction |
|
| 48:50 | into the SOMA. So these micro highways are very important for transportation because |
|
| 48:59 | happens if we take 45 entangle it I 10? It's a big |
|
| 49:08 | right? So what happens if there traffic on 290 it's gonna take you |
|
| 49:15 | hour to get home versus 20 Don't go through Galleria 610, |
|
| 49:26 | As always traffic, you can try 3 a.m. maybe still a little traffic |
|
| 49:32 | ami guarantee you it might be smooth . So all the rest of the |
|
| 49:37 | . So the point that I'm making that if something happens in these micro |
|
| 49:43 | highways, if there is a jam gene such as what happens in Alzheimer's |
|
| 49:50 | , you lose the axonal trans, you entangle these elements, you cannot |
|
| 49:57 | things properly. So it may still and I have gotten wrapped around, |
|
| 50:02 | can still go through that. But it may take you 20 times longer |
|
| 50:07 | get to your final destination. So are very important uh for the functionings |
|
| 50:13 | the cell axons that we already started are pretty interesting. The axon hillock |
|
| 50:20 | where the action potential forms and this the beginning of the axon, this |
|
| 50:25 | the proper axon proper and a lot times axon may have its terminal destination |
|
| 50:30 | distance farther away, but it may these collaterals closer to its SOMA and |
|
| 50:38 | synopsis closer before it reaches its own and axonal terminal, there are some |
|
| 50:46 | between axons and SOMA. Obviously, are differences in protein composition. So |
|
| 50:53 | are certain protein channels that are present dendrites and not present in selma, |
|
| 50:58 | that are present in selma and not in axons. So it's a unique |
|
| 51:04 | of these proteins, subcellular dendrites will a certain types of protein Somas, |
|
| 51:11 | axons, uh yet other ones, er, does not extend to an |
|
| 51:18 | . Ok. The cosmic reticulation external . And again, what you're seeing |
|
| 51:27 | is that at the axon terminal, is the site where synaptic transmission |
|
| 51:33 | What you have is these external terminals loaded with mitochondria because vesicular release, |
|
| 51:42 | , exocytosis is vesicular release, fusion uh neurotransmitter release, exocytosis, endocytosis |
|
| 51:52 | that, that vesicle back, recycling chemicals to transport us back, refilling |
|
| 52:00 | vesicles, getting those vesicles primed in active zone. So they can be |
|
| 52:05 | fused to release their content. This a lot of energy and renew all |
|
| 52:10 | that energy at the synoptic terminus. that's where you see a lot of |
|
| 52:14 | mitochondria. So at the Axion initial here and now this is really |
|
| 52:22 | But at the Axion initial segment, you generate this action potential here, |
|
| 52:32 | action potential travels all the way to axonal terminal, right. And this |
|
| 52:40 | potential which is electrical causes the release neurotransmitter which is chemical, this neurotransmitter |
|
| 52:54 | to postsynaptic receptors will again cause a in the membrane potential. It becomes |
|
| 53:04 | . So electrical action potential causes the of the chemical chemical binding of the |
|
| 53:10 | receptors will cause a depolarization a change the membrane potential. Ok. |
|
| 53:20 | synaptic transmission is very important. Normal transmission, endocytosis of the vesicles reabsorption |
|
| 53:30 | transport and reuptake of the neurotransmitter that been released back into the pre synoptic |
|
| 53:35 | is very important. And there are dysfunctions and neurological disorders that can result |
|
| 53:42 | abnormal synoptic transmission and it could be chemicals that are involved. So when |
|
| 53:49 | talk about Parkinson's disease, for we will mention dopamine. It's a |
|
| 53:55 | dopamine synaptic transmission. It's a certain in the brain. When we talk |
|
| 54:02 | um clinical depression or anxiety, we about another chemical that is serotonin and |
|
| 54:12 | . With serotonin synaptic transmission is going be impaired and the synaptic transmission is |
|
| 54:19 | just how much of a chemical you and how well you release it and |
|
| 54:24 | . It's also what is happening to po synoptic receptors targeted by these |
|
| 54:31 | As a part of the disease, could be impairment in both the release |
|
| 54:36 | and also the posy response machinery due the faulty receptors that are psyop and |
|
| 54:44 | can lead to neurological disorders. Different and different chemicals would be associated with |
|
| 54:50 | neurological disorders. Epilepsy is typical and imbalance of glutamate and Gaba. Although |
|
| 54:57 | chemicals are also implicated and involved and study all of them in this |
|
| 55:02 | So you'll understand exactly what we're talking in just a few lectures. So |
|
| 55:08 | axonal transport can be taken. Advantage axonal transport is really good if you |
|
| 55:13 | to, for example, know I'm here at this piece of the brain |
|
| 55:18 | this piece of the skin. Let's I'm looking at this piece of the |
|
| 55:21 | , I want to know what neurons commu communicating to to this area |
|
| 55:27 | So I can use a dye. is horseradish peroxidase. I can inject |
|
| 55:34 | guy into the tissue or ceramic peroxidase specifically get taken on by axons and |
|
| 55:41 | is called retrograde transport. So, transport is from the selma to the |
|
| 55:46 | . Retrograde transport is from the from the exon terminals back into the |
|
| 55:52 | . So because I injected this hr dye here, the neuron axons will |
|
| 55:58 | this dye over here and we will them to the selma. And now |
|
| 56:03 | know that these neurons are the ones are communicating to this network right |
|
| 56:09 | right. This is just a simple that's actually a lot more complex than |
|
| 56:15 | work that we will probably reveal with . So horse riding peroxidase is a |
|
| 56:21 | is a tracer viruses such as herpes and rabies virus are capable of the |
|
| 56:30 | transport, retrograde transport. So they appear, let's say in the periphery |
|
| 56:37 | the nerve and enter into the neurons the processes such as axons. There |
|
| 56:46 | some viruses. When we talk about system, we're gonna talk about her |
|
| 56:51 | virus that causes chickenpox. And then life can reemerge as shingles. That |
|
| 56:59 | is capable of moving both directions. capable of moving anterograde and then it's |
|
| 57:06 | of moving retrograde. So there are that will move both directions and we |
|
| 57:14 | take advantage of them not to infect to infect to trace in a controlled |
|
| 57:20 | . This is not a, you use a virus that you can tag |
|
| 57:24 | a visible marker, fluorescent marker and can trace where that virus travels through |
|
| 57:30 | tissue and that can reveal a lot the connectivity and the projections in these |
|
| 57:37 | . Yeah. How do the viruses travel? How do they travel? |
|
| 57:42 | infect the cells? But it's a question because they may have their own |
|
| 57:47 | mechanisms. Yeah. Yeah, it be that they hijack a transporter protein |
|
| 57:57 | in many cases, we don't even the precise mechanisms. Yeah, but |
|
| 58:02 | can start replicating and maybe spreading even without active transport. But it's a |
|
| 58:07 | question. I actually don't know a answer for that. All right. |
|
| 58:14 | . So we will finish by talking Alzheimer's disease and how it relates to |
|
| 58:20 | we're talking about cyto skeletal elements. let's talk about Alzheimer's disease. How |
|
| 58:27 | of you heard of Alzheimer's disease? many of you heard of Alzheimer's disease |
|
| 58:33 | N PR or television? I have they have some new, yeah, |
|
| 58:41 | . There's some new treatments and technologies out to help with Alzheimer's disease. |
|
| 58:47 | do you, what comes to mind you think of Alzheimer's disease, |
|
| 58:52 | which is means what symptoms of dementia forgetting? Ok. So you're thinking |
|
| 59:02 | memory loss, forgetting. Ok. good. So, what, what |
|
| 59:05 | that? That is a symptom. right. And, um, an |
|
| 59:12 | of Alzheimer's disease is typically in people are 55 or older. It's a |
|
| 59:19 | . It's not a normal process of because you have plenty of people in |
|
| 59:24 | nineties that don't have Alzheimer's disease and 100 years old. And you have |
|
| 59:29 | in fifties that have Alzheimer's disease, progression. What is the disease |
|
| 59:38 | We already mentioned, symptoms, symptoms something that you observe. So, |
|
| 59:44 | you come into neurologist's office and you your older parent or grandparent, you |
|
| 59:51 | something is wrong, they're not not remembering some things. So they |
|
| 59:56 | test you for loss of memory. at first, it's a short term |
|
| 60:03 | that people lose. So at early , when you first get the |
|
| 60:09 | you may have lapses of short term . So you will interact with somebody |
|
| 60:14 | you will come back two hours later say like, did we just talk |
|
| 60:17 | this? I can't remember anything. can't remember what we talked about. |
|
| 60:21 | know, you really can, uh then it becomes progression of the |
|
| 60:27 | it becomes progressively worse. So if disease is not being controlled and Alzheimer's |
|
| 60:32 | , you can only slow down the of the disease with existing with the |
|
| 60:37 | medications, you cannot cure Alzheimer's. what is this progression? The progression |
|
| 60:44 | that things get worse from short term loss. At first, you don't |
|
| 60:49 | short term things, but you still your children's names, your major events |
|
| 60:55 | street names and then it starts affecting long term memory. And at some |
|
| 61:00 | , people with Alzheimer's disease, they remember anybody that is talking to |
|
| 61:05 | Sometimes they don't even recognize that It would be very sad for, |
|
| 61:10 | , for the, for the clothes loved ones to experience that loss of |
|
| 61:15 | essentially. But there's other things, anxiety, there's disorientation because how, |
|
| 61:22 | , how panicky do you get if like, don't remember something, you |
|
| 61:25 | find something. You know, you to go on the trip someplace I |
|
| 61:28 | can't find, oh my God. know, I'm gonna have to turn |
|
| 61:31 | my whole closet and see if I find that thing. And it's, |
|
| 61:34 | , it stresses you out. You're . Now, imagine this every day |
|
| 61:38 | everything you're doing. You can't find . You don't remember what it |
|
| 61:43 | You don't understand this. Is this I use for painting or is this |
|
| 61:48 | I eat? There is disorientation, spatial disorientation this time, disorientation. |
|
| 61:56 | grandmother that had Alzheimer's disease, one my grandmother's had Alzheimer's disease. She |
|
| 62:02 | walk out at 11 a.m. because in countries, she lived in Lithuania in |
|
| 62:11 | and the summertime 10 a.m. 10 PM sometimes 10:30 p.m. is live outside. |
|
| 62:19 | summers are very long and the days very long. So she would walk |
|
| 62:22 | around 10:30 p.m. go to a market farmers market to shop and then she |
|
| 62:31 | see no people on the streets and would say what's going on, where |
|
| 62:35 | everybody and you know, her neighbor she would call us and would |
|
| 62:40 | well, everybody is probably asleep, it's a dis disorientation of time, |
|
| 62:46 | of space uh where you're going. It's a terminal disease with no |
|
| 62:53 | It can also have comorbidities that forms is another disease that forms as a |
|
| 63:00 | of Alzheimer's disease. So some processes happens the pathological processes during Alzheimer's |
|
| 63:08 | it's almost like recruits another disease and called comorbidity. So people with Alzheimer's |
|
| 63:15 | have a very high likelihood of having . It's called comorbidity because now you |
|
| 63:22 | two things killing you co morbid. Alzheimer's is killing you causing neurodegeneration and |
|
| 63:32 | could be killing you co together with disease. So this is a lot |
|
| 63:39 | clinical stuff, symptomology, things like . We're not gonna get into treatment |
|
| 63:45 | . We're gonna get into treatment when study acetylcholine system. But these are |
|
| 63:49 | major cellular and network pathological hallmarks of disease. And this is how it |
|
| 63:56 | to what we just talked about is have the formation of these beta amyloid |
|
| 64:01 | that are extracellular and as they start , they actually physically start secreting things |
|
| 64:08 | are bad for neurons impinging on their and eventually causing the axons to degenerate |
|
| 64:16 | not being able to communicate to each . So, these are extracellular |
|
| 64:20 | it's almost like calcified plaques, be plaques. A lot of times we'll |
|
| 64:25 | senile plaques or dementia plaques. That's the beta amyloid plaques are. And |
|
| 64:30 | on the outside, on the you have information of neurofibrillary tangles where |
|
| 64:37 | have over expression of the TAU which basically accumulates on the microtubules and |
|
| 64:45 | the SOMA and causes those tangles. go back to this slide and think |
|
| 64:51 | what happens if I tangle my cyto elements with neurofibril and stuff like |
|
| 64:58 | I get that 45 wrapped around I cannot deliver goods. There's traffic |
|
| 65:03 | , there's very poor transportation. The is being killed from inside. |
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| 65:09 | with neurofibrillary tangles and if you have plaques, the cells are being killed |
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| 65:16 | outside with the plaques. So the amyloid uh forms extracellular top protein entangles |
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| 65:24 | intracellular at the advance stages of Alzheimer's . You have a severe neurodegeneration of |
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| 65:31 | brain. And this is a illustration a healthy brain next to the hemisphere |
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| 65:38 | from Alzheimer's brain patients. So you a lot of neurodegeneration, shrinkage of |
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| 65:44 | brain loss of particular gray matter. a lot of gray matter is lost |
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| 65:50 | some white matter. A lot of matter that is still left. |
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| 65:53 | this is gross pathological level. cellular level two major things that are |
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| 66:03 | inside the cell tangles outside the cell envelope plaques with growths. You have |
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| 66:10 | changes. You have shrinkage of the loss of gray matter and the more |
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| 66:16 | the plaques, the more of the , the more of the progression of |
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| 66:19 | disease you have, the more of symptoms, you are collecting, those |
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| 66:25 | are worsening and you're potentially forming or a comorbidity on top of that |
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| 66:33 | what happens is, it's not just remembering things, it's about your brain |
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| 66:39 | being able to sustain the vital functions your body. An individual loses the |
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| 66:44 | of scent, smell, sometimes taste and your brain cannot no longer |
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| 66:52 | things like swallowing or even breathing. that's what the terminal end of Alzheimer's |
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| 67:00 | , is your brain function completely collapses the at last stages of Alzheimer's. |
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| 67:05 | I'm gonna end here today if you mind, hold your question until next |
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| 67:10 | or you can ask me afterwards. , have a great weekend. I'll |
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| 67:14 | everyone here on Tuesday and I'll have lectures ready then. Thank you guys |
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| 67:19 | paying attention, |
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