| 00:00 | this lecture. This is lecture four neuroscience. We discussed neurons and |
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| 00:06 | We discussed major organelles and structure of , highlighting some of the features such |
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| 00:13 | dendrites and dendritic spines. My eliminated and synapses with external terminals. We |
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| 00:21 | about very basic concepts and very quick of transcription and translation and discuss the |
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| 00:27 | cesareans, normal and pathological supplies, . Basic organelles are up in the |
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| 00:33 | particular production of protium. And then talked a little bit about the micro |
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| 00:38 | which are essentially synthetic wells wells filled synthetic DNA. And you have thousands |
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| 00:45 | these little specific sequences of synthetic DNA in each well. And this micro |
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| 00:51 | of these wells that can contain thousands them can help you track which genes |
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| 00:57 | over expressed under expressed and any one the conditions, normal versus pathological condition |
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| 01:05 | and also in different parts of the . So it gives you a good |
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| 01:09 | eye view of profiling differences. Some expression as a consequence of let's say |
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| 01:14 | brain injury. For epilepsy ah smooth the plasma particular um large stores of |
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| 01:21 | golgi apparatus, protein folding for their destination mitochondria in the brain is very |
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| 01:28 | because as we talked about it, a nonlinear system. It's driven outside |
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| 01:33 | the equilibrium and a few percentages of mass of the brain from prizes compared |
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| 01:38 | the overall mass of the body. brain consumes 20% of all of the |
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| 01:43 | and so mitochondria in or where you the production of the major energy source |
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| 01:48 | teepee and the core molecule of ADP denison because the T. P. |
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| 01:52 | for Dennis and fred phosphate, a is also a neurotransmitter chemical in the |
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| 01:57 | . You'll learn about that later. watched the quick movie about how fluid |
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| 02:04 | plasma membrane is and how the mosaic the composition of different proteins and |
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| 02:13 | fats and cholesterol's within the cross plasma and associated with plasma membrane changes and |
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| 02:20 | these trans membrane proteins and neurons can moving very fast fashion to review the |
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| 02:26 | , political violator basics and underneath the structure in general supporting the overall structure |
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| 02:33 | the south and the shape of the either side of skeletal elements. So |
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| 02:39 | tubules, the largest neural filaments or filaments and micro filaments comprised of active |
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| 02:46 | and micro tubules, as you can here in the axons are responsible these |
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| 02:50 | for micro tubular transport. You'll see the turbulent is expressed closer to the |
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| 02:58 | at the core structure of the cell that the oxygen molecules from blue actually |
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| 03:03 | in the periphery closest to the membrane shaping the kind of overall outer shape |
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| 03:09 | the plasma membrane. For Alzheimer's For hallmarks of Alzheimer's disease, we |
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| 03:16 | reviewed the different slide and what I've you to do is ask you to |
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| 03:21 | taking no. So if I asked to take notes and to write down |
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| 03:28 | things and to start developing this colorado language if you may about the |
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| 03:35 | So the prevalence of the disease, definition of the disease. So please |
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| 03:40 | Alzheimer's disease. It's a dementia The prevalence c occurs in the |
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| 03:47 | What are the causes of Alzheimer's There is a genetic component meaning that |
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| 03:52 | you have somebody in the family you're likely to develop Alzheimer's disease, but |
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| 03:58 | not always the case. Um It's mixed bag of things. Uh but |
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| 04:03 | is a lot of the Alzheimer's disease is sporadic. That just because it's |
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| 04:08 | doesn't have a genetic component necessarily. On the pathology side, on the |
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| 04:15 | side we discussed intracellular neuro regularly tangles will impair inside the cell intracellular transport |
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| 04:24 | communication on the outside of the You have the formation of beta amyloid |
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| 04:30 | and these plaques will start binging physically neurons and affecting especially the acts on |
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| 04:36 | hill are the location where action potentials produced, causing neural degeneration. So |
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| 04:41 | gross anatomical scale and the violence to disease phases. You have significant loss |
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| 04:48 | degeneration of brain tissue, gray white matter and shrinkage overall in the |
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| 04:54 | . The formation of these flax and shrinkage or loss of the neurons and |
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| 04:59 | rest of the pathology eventually results in brain not being able to take care |
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| 05:03 | itself in the body and sad So this is Alzheimer's disease. And |
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| 05:10 | take these notes and please uh make that you keep track of this page |
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| 05:17 | we'll come back to this page and about Alzheimer's disease when we talk about |
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| 05:21 | Conan neural transmission in the brain and make sure that I will upload this |
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| 05:26 | on your lecture material in here. we talked about dendrites and dendritic spines |
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| 05:34 | important they are. And we talked the whole synapse and how the axon |
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| 05:39 | external terminal will contain mitochondria synaptic neurotransmitters within these vesicles that will get |
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| 05:46 | in the synaptic flat and will cause possum haptic response. There are slugs |
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| 05:51 | plasmid transport and past acts of plasma . That saying that will be |
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| 05:57 | Interrogated transport and dining in that is for retrograde transport. We talked about |
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| 06:03 | retrograde transport. You can use to advantage of those molecules chemicals such as |
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| 06:12 | , peroxide or viruses that have the to travel retro greatly and get absorbed |
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| 06:18 | the stillness of the neurons of So you can then label which part |
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| 06:22 | the brain which part of the skin my salt is being served by certain |
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| 06:29 | such as these H. R. . Labeled neurons. Dendrites and dendritic |
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| 06:36 | . We talked about how there's different of the dendritic spines and those dendritic |
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| 06:41 | is the site where most of the takes place and the proper formation of |
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| 06:47 | densities of dendritic spines of the shape the dendritic spines and locations along with |
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| 06:52 | shafts are very important for normal learning and plasticity. These are PSD stands |
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| 06:59 | post synaptic densities under good experience that contain the boston athletic receptors. There's |
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| 07:06 | in here, Dendrite and Jackson posted red axon labeled vesicles containing neurotransmitters and |
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| 07:18 | shapes of these dendritic spines. In to containing mitochondria, dendritic spines also |
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| 07:24 | Paula reverse thermal synaptic complexes and these follow rebels. Although complex is enabled |
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| 07:31 | the good experience to be somewhat biochemically . Dendritic spine, normal development. |
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| 07:38 | down cities and distribution along gun rights very important in some instances mental retardation |
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| 07:48 | developmental disorders. Mental retardation are associated abnormal formation of these dendritic spines. |
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| 07:57 | when we talked about some of the things like mental degradation and we talked |
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| 08:06 | Alzheimer's disease and also introduce you to spectrum disorder. And autism spectrum disorder |
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| 08:17 | social, the behavioral developmental abnormalities. referred to autism spectrum disorders as developmental |
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| 08:27 | because usually occurs in the first two of life. But there is also |
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| 08:32 | that can get diagnosed in adults but . Um And in autism spectrum |
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| 08:40 | There is other syndromes and other conditions also exhibit the features of autism spectrum |
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| 08:48 | and by the way, a lot autistic Children and adults of course they |
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| 08:54 | not only negatively impacted by not having to have proper social interactions and proper |
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| 09:03 | . A lot of times it could repetitive behavior stuck on doing something and |
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| 09:09 | it could be also self injured. some of the autistic Children have the |
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| 09:18 | feature of injuring themselves hurting themselves which hitting themselves. And sometimes they have |
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| 09:23 | wear helmets and stuff at the same . Uh Some of the autistic Children |
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| 09:29 | adults are incredibly talented and they have ability to have these almost genius like |
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| 09:39 | to remember details to factual details to great degree. I went to college |
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| 09:48 | autistic statistic uh colleague of mine and taught himself Hungarian which is the most |
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| 09:58 | language in the world to learn and self teach especially. And he knew |
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| 10:07 | of the presidents of all of the countries for the entire 20th century. |
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| 10:15 | So it had this incredible ability to that information but a lot of times |
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| 10:21 | that individual had difficulties was to making of that information so to speak or |
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| 10:30 | metaphorically about that information or um not able to go beyond the factual knowledge |
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| 10:40 | to then understanding certain other things behind conflicts or the changes that happen political |
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| 10:49 | in an african time for example. it's it's positive too. But it's |
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| 10:55 | obviously a disorder that is being treated behavior. And then of course there |
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| 11:00 | therapeutic treatments for other associated things that with autism may experience such as anxiety |
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| 11:11 | A. D. H. Or like I said there's self injurious |
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| 11:15 | . And so the different drugs are to treat those kind of conditions and |
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| 11:19 | behavioral and social um enrichment environments and of being used to improve the behavioral |
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| 11:28 | of the disease. So keep keep writing on this page about awesome autism |
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| 11:35 | disorders. Because we also introduced a called fragile X syndrome. And the |
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| 11:42 | why we talk about fragile X syndrome because fragile X syndrome has a fragile |
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| 11:50 | chromosome, fragile X syndrome. There a gene that is called F. |
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| 11:57 | . R. P, frank mary , paul, M F. |
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| 12:02 | P. And F. R. . Protein. Actually in the film |
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| 12:07 | ex uh gene and this gene has functions in the brain and the body |
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| 12:15 | in neurons. One of its functions regulating the normal formation of these spines |
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| 12:23 | normal formation configuration densities the location of dendritic spines. Now, fragile X |
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| 12:34 | Children have autism syndrome like disorders. they have some of the potentially social |
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| 12:42 | non covered ordination. But they also have other severe symptoms. And the |
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| 12:49 | fraction of the fragile likes Children where experiencing epilepsy and seizure. So what |
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| 12:59 | will do also is there is a good link on cradle X syndrome. |
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| 13:11 | Center for Disease Control's okay. And you go to this, there's a |
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| 13:18 | of the Children with fragile X syndrome one of the outward um anatomical features |
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| 13:27 | these Children are these elongated ears usually very long and very large foreheads and |
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| 13:38 | long faces. Now it is not say that because you have those features |
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| 13:43 | that that somehow there is a FM protein gene disorder. You have some |
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| 13:49 | of a thing going on with fragile because I have some friends that have |
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| 13:56 | years and big foreheads and they don't any of these conditions. So, |
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| 14:00 | this is one of the outward features you can experience with with the fragile |
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| 14:06 | syndrome. What is fragile X Is that the CDC website? Now |
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| 14:12 | , when you search for information and search for information on life, please |
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| 14:16 | sure it's from the credited medical uh , not from just google or it |
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| 14:26 | from the peer reviewed articles and reviews Top man, not just a news |
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| 14:33 | or opinion on the radio or something that. So, fragile X syndrome |
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| 14:39 | a genetic disorder. It's a developmental disorder. Now this is very different |
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| 14:47 | when we compare that with Alzheimer's FMR one gene is responsible for making |
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| 14:54 | protein of MRP and this FMR PEA is needed for brain develops. Uh |
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| 15:01 | people that have fragile X syndrome do make this protein and people who have |
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| 15:06 | fragile X associated disorders, they have in the FMR one gene, but |
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| 15:12 | make some of the protein. So seems that it depends if you have |
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| 15:17 | gene on the fragile X chromosome completely and you're not making any protein at |
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| 15:24 | , then there seems to be linked the severity of the disorder. And |
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| 15:27 | you're making some of that FMR PEA and maybe some of the part of |
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| 15:32 | FMR our gene sequences still functional for for transcription and translation. Then you |
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| 15:40 | then capable of having milder syndromes And we can go on talking about |
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| 15:47 | long time about these syndromes but we we will stop at this. But |
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| 15:53 | is a really good example because in condition of mrp gene protein would be |
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| 16:00 | the proper formation of the british Ah And as you recall, these |
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| 16:06 | will be receiving a lot of the . They will be receiving a lot |
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| 16:10 | the synaptic inputs from the glutamate excitatory . So the major neurotransmitter in the |
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| 16:16 | that is excited to is glutamate and from the major inhibitory synopsis which is |
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| 16:24 | is the major inhibitory neurotransmitter in the . And so the work of this |
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| 16:29 | is to integrate through the democrats and synaptic connections all of that information into |
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| 16:34 | cell for that self the function normal produce action potentials. So you can |
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| 16:38 | if you compare the distribution of dendritic , the shapes or their plasticity then |
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| 16:43 | very much affecting this interactions and balance thousands of the excited too and thousands |
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| 16:49 | the inhibitory inputs that are communicating in different neurons. There was a couple |
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| 16:55 | slides that repeated repeated here. There four functional regions in neurons. There |
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| 17:02 | an input region. It could be model neuron from the skin. |
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| 17:05 | your local interneuron projection into neurons when under queen style there's an integrated region |
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| 17:12 | is the soma. So once the come in and most of the inputs |
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| 17:15 | neurons that we discuss actually will come under the gun rights and then eric |
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| 17:20 | . So most there is some inputs will also with the exception contact axons |
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| 17:24 | most of them rises and expands and information from these emphasis then integrated in |
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| 17:29 | selma. It is conducted through its . I'll unit along here where the |
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| 17:35 | potential is producing acts on initial segment it is being conducted through the axons |
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| 17:41 | these accents are my eliminated violin ated preserve the conductivity of the electrical |
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| 17:47 | But in some instances there are neurons local inter neurons that are unknown Myelin |
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| 17:52 | So they don't have violent sheets covering accident. In some instances sensory neuron |
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| 18:00 | is dorsal root ganglion cell has a acts on going into the skin joints |
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| 18:05 | muscles. And peripheral axon carries information the selma which integrates that information and |
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| 18:11 | conducts it to conduct our central acts into the output region on to the |
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| 18:19 | the motor neurons in the spinal cord you will learn later and the output |
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| 18:24 | can be secretion onto another neuron onto style and even unto the micro |
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| 18:30 | Uh influencing the basil constriction and dilation the micro capillaries through the neuro |
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| 18:38 | through the neuronal communication. So now said okay we have major two classes |
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| 18:45 | cells. Excitatory cells and excitatory cells glutamate and inhibit their cells and inhibit |
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| 18:51 | cells release gaba. These are major of self that we have in the |
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| 18:56 | . But The neurons there are over different subtypes of neurons. Today you |
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| 19:03 | learn at least about five different subtypes we ourselves too. So how do |
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| 19:09 | know that there are 150 different subtypes neurons in the And how come there |
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| 19:15 | 100 and 50 different types of nerves the brain? Remember that all of |
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| 19:19 | cells in your body such as the , consult neuron, leah you name |
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| 19:27 | . They all have the same genetic . Only a subset of genes based |
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| 19:34 | the environment. Developmental coding gets And as it gets expressed to get |
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| 19:41 | morphology, you get different expression uh different functionality in these cells that you |
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| 19:48 | now classify and distinguish between different types neurons. So the way that we |
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| 19:54 | classify neurons on the gross and microscopic would be you're looking at their |
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| 20:01 | Some of the salsa Unipol are. are characteristic in Martinsburg Sauls. They |
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| 20:06 | branches of one axon looking into one . So this is selma axon and |
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| 20:12 | and both are pointing north into the pole bipolar cells bipolar cells from many |
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| 20:19 | cells such as retinal bipolar cells that were learning the retinal sort of olfactory |
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| 20:26 | themselves. That you will also learn the old factory system and spinal cord |
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| 20:33 | bipolar ourselves to so you have these cells that have done right And that |
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| 20:39 | pole is north that has soma and axon is in the south pole. |
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| 20:46 | why it's black gold dorsal root ganglion , mechanical receptors that carry information from |
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| 20:54 | skin joints and muscles of touch, , pressure and enter into the spinal |
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| 21:00 | , studio unit polar cells of dorsal ganglion cells. Those are the cells |
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| 21:04 | will have what I was talking about peripheral axon going into the peripheral and |
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| 21:10 | axon contracting on the neurons. And studio unit polar cell, peripheral |
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| 21:15 | the skin or muscle and then the axon to ganglion cell, dorsal dorsal |
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| 21:22 | , angry and salad dorsal root. these external terminals will end up in |
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| 21:26 | spinal cord, contacting motor neurons and neurons. You will learn about that |
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| 21:31 | in the next lecture I believe. unit polar selves. And now most |
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| 21:37 | the neurons that will be discussing in brain are multipolar neurons. This is |
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| 21:41 | predominant type of neurons in the brain multiple polls or north south east |
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| 21:48 | north east, south, east, , southwest, northwest and so on |
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| 21:54 | motor neurons. For example. This motor neuron office spinal board Spinal motor |
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| 22:00 | in the spinal cord can receive 10,000 . So somebody I believe in this |
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| 22:07 | had a question of how many cells a single dorsal root ganglion and I |
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| 22:13 | it was assad. I'm not sure many, I haven't had a chance |
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| 22:17 | look it up. Maybe you can it up, but this is how |
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| 22:21 | synapses a single motor neuron can and in the spinal for 10000s announced |
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| 22:29 | optical parameter cells, parameter cells. they have the optical done right on |
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| 22:35 | and basil done right coming out of bottom. So they're called pyramidal cells |
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| 22:41 | they look like pyramids. Their structure like a government structure. This is |
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| 22:47 | apex the top, this is the of the pyramid. And this is |
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| 22:51 | axon. These are typical hippocampal cells you'll learn a little bit about the |
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| 22:56 | today there's a hippocampus and hippocampal circuit it's also the major excitatory cell. |
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| 23:07 | mineral cells in the cns. So will find these parameters cells throughout the |
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| 23:13 | as well. Now look at this on the right, this is a |
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| 23:18 | Kinji cell of sarah bone And this can receive up 250,000 synopses has an |
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| 23:31 | branching of the dendritic tree the selma the axon hugely multipolar and has the |
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| 23:39 | to compute It's a process of information 150,000 synopsis. And this massive and |
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| 23:46 | branch. So there is another way classifying neurons and most of the neurons |
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| 23:53 | we're talking about that abdomen droids will dendritic spines so they're spiny. But |
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| 23:58 | are some exceptions and there are some that do not really exhibit that same |
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| 24:04 | of dendritic spines. You can see gun rights are smooth, they don't |
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| 24:09 | these protrusions, It doesn't mean there a pathological condition, but just some |
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| 24:14 | them neurons in the brain are a . Now. Finally in the 1930s |
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| 24:23 | 1940s there is enough of the technological that allows for the creation of fastest |
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| 24:31 | . And as the fastest Silas groups created, scientists start using these oscilloscopes |
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| 24:37 | record electrical activity in the muscles and nerve tissue. The development of this |
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| 24:45 | was actually confirmed with the wars that going on in the world of World |
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| 24:50 | Two and a lot of this fast circuits were developed by militaries around the |
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| 24:59 | . The the japanese Russian and american so on. And so us maybe |
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| 25:08 | is developing really cool fastest telescopes would in c connectors and you'll have them |
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| 25:14 | in submarines and will happen in the labs with BNC cables connecting the oscilloscopes |
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| 25:20 | amplifiers and such and the electors and Hodgkin Huxley publishes in 19 39, |
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| 25:27 | first recorded action potential. So this for control is a deflection from about |
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| 25:34 | 60 million volts here to about plus million volts. It's very fast. |
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| 25:40 | only about one to few milliseconds in . That's when you need it very |
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| 25:44 | . Electrical electronic circuits in order to up that information And display that information |
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| 25:50 | the screen. And once that action was displayed on the screen, it's |
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| 25:56 | . It's not like you can send email, take a snap of |
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| 26:00 | There's no mobile phones. 1939. things that we have in hand |
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| 26:04 | just think about how people were operating years ago. How were people making |
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| 26:10 | phone call 100 years ago. Through a radio person. I mean through |
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| 26:23 | through and dispatcher right, I took the call and say can you connect |
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| 26:28 | to so and so just like you 300 lines in the city connecting 400 |
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| 26:34 | numbers. Whatever they have to A Polaroid picture of this telescope and |
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| 26:39 | is a Polaroid picture of this telescope basically this first reported published and the |
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| 26:45 | of the reporting of the action So apart from classifying neurons based on |
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| 26:51 | morphology, we can also classify neurons on their productivity. Some of the |
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| 26:56 | and projection cells and they will project axons long ranges long distances and will |
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| 27:02 | adjacent cells and other cells are inter . That means that they will be |
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| 27:07 | locally in the network and will not projecting long ranges or long distances. |
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| 27:12 | classification based on connectivity. Most of projection cells in the brain are |
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| 27:18 | very prominent all cells of glutamine and neurons are inhibitory local network cells that |
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| 27:26 | Gaba inhibitory neurotransmitter and therefore this is excitability, the cells that are releasing |
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| 27:33 | , excitatory, the cells that are and releasing Gaba inhibitory cells. But |
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| 27:39 | that, that's not enough because there's variety of the huge variety of the |
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| 27:46 | inhibitory cells. So it's not enough say that inhibitory cells just synthesize |
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| 27:51 | but you have a variety of So you have to identify cell specific |
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| 27:57 | that sees these cells may produce, I mentioned that each self satisfied expresses |
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| 28:04 | subset of genes which ends up in it a unique subset of specific markers |
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| 28:10 | , Such as neurotransmitters and Europe are and you have to stay in Poland |
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| 28:14 | order to distinguish between what I'm talking 150 or or less subtypes of cells |
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| 28:21 | on the area of the circuit of brain. You're looking at. |
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| 28:25 | those cells, as we see are not silent that produce action potentials |
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| 28:31 | because they express different proteins, different and they have slightly different number and |
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| 28:36 | , they will produce different firing So when we say action potential, |
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| 28:42 | an action potential, we refer to fast electrical potential that happens and that |
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| 28:48 | is a sequence of these actions for and the frequency and the amplitude of |
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| 28:52 | sequences vary across different cell subtypes because dependent on the specific molecules from proteins |
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| 29:00 | these cells express which brings us to circuit. This is a really cool |
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| 29:07 | . This is a circuit off the . This is a very important part |
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| 29:12 | the brain that is involved in memory and the memory recall. That's our |
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| 29:18 | cortex. It's archaic cortex. It three predominant players stratum ready adam. |
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| 29:24 | white layer here stratum for Madeline and bottom layer striving for you. So |
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| 29:32 | uh in the brain is only a centimeters in size and this is one |
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| 29:40 | of the upper Campbell is called the . A. One area of the |
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| 29:44 | . And for now what you have pay attention to this course is the |
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| 29:50 | . If you look in the hippocampal . You know this is there a |
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| 29:54 | cells? These are projection parameter cells project their axons out of the hippocampus |
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| 30:00 | they're excitatory cells. And you can that most of the parameter cells actually |
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| 30:06 | be dominating stratum from the Dallas and of the parameter ourselves will be very |
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| 30:11 | packed from the stratum from the dalai . So it's stratum as a layer |
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| 30:16 | the Dallas after the tournament's parameter yourself the parietal sauce of sitting in this |
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| 30:23 | layer are labeled here C. Plus that means that they contain a |
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| 30:29 | cell marker Calvin did their positive for . There are other parameter cells. |
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| 30:34 | not much different than their shape. also production cells but they are located |
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| 30:39 | the perimeter layer and they're called bending . But all of these cells collectively |
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| 30:44 | actually excited their criminal cells that will that information onto the adjacent circuits or |
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| 30:51 | of the hippocampal surface, right in hippocampus. These parameter salsa doesn't don't |
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| 30:57 | very diverse and their morphology, they're in the parameter layer. Some are |
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| 31:04 | and the only saw market is different dependent not very diverse self population but |
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| 31:11 | brain is capable of producing many different and many different dynamical modes performing in |
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| 31:20 | different dynamical modes. And so when look closer here there's 1234 all the |
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| 31:26 | to 21. What are these? are inhibitor in general. What does |
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| 31:33 | mean? That means that in this example circuit There's only really two. |
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| 31:40 | really even to the the difference of . B. Positive or negative |
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| 31:46 | So it's kind of a really like excitatory subtype of self That is being |
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| 31:52 | locally in the circuit by 21 some of the inhibitor. And so you |
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| 31:58 | see that the psalms of these inhibitory like 12456 and 1921 are in the |
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| 32:06 | of Some of the SEA are in bottom layer. Orients which was 7:15 |
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| 32:11 | example. They have their dendrites in and red. So you can see |
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| 32:17 | some of the dendrites are spanning across three layers vertically. And some of |
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| 32:25 | damned rights like in red here Are horizontally and are staying within one |
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| 32:35 | So there is a very clear differential the morphological features between let's say cell |
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| 32:42 | seven and cell number one. It's so no location, it's their damn |
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| 32:48 | . But that's not enough. So yellow cops that are shown here these |
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| 32:53 | cops uh the synapses. These are external terminals and it shows where some |
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| 32:58 | the cells will contact parameter all cells their applicable done brides like this number |
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| 33:05 | cells. Okay well target africa Den of the parameter will sell. So |
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| 33:10 | are the yellow cops will be the the external terminals and in the Haram |
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| 33:14 | cells And a lot of the engine like two and 3 and four will |
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| 33:19 | Selma's very densely packed parameter layer to very tight control inhibiting the activity at |
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| 33:28 | level of the soma and around the which was called paris somatic region. |
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| 33:35 | again you have very clear distinct wishing between some of the cells. So |
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| 33:43 | soma. Dendrites are vertical and these cops are somatic seven Dunn drives |
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| 33:51 | You have axon targeting a pickle and lives in a different place. But |
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| 33:58 | you look at two and four, don't look very different because why? |
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| 34:04 | they have the same soma the same projections that are vertical, the same |
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| 34:10 | of projecting to the paris somatic regions parameter cells. So what is different |
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| 34:15 | two and four? Number two is basket cell That is P. |
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| 34:19 | It's provocative and positive. It's called basket cell because it's sort of like |
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| 34:23 | looks like a basket And # four another type of Basque itself. That's |
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| 34:30 | and V Blue three positive. And are internal cell marker. CCK stands |
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| 34:35 | scholars is too kind for example. , so what information do you need |
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| 34:42 | know from the slide? Because there's lot of information on talent and what |
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| 34:48 | telling you is in order for you distinguish and to definitively prove that you're |
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| 34:54 | cell number seven was the cell number inhibitory cell and this is the kind |
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| 34:59 | complexity that you have to know. you have to experimentally prove as neuroscientists |
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| 35:08 | you're performing your work. In other , if you just do some recordings |
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| 35:12 | the hippocampus, I just stabbed themselves recordings and you try to publish that |
|
| 35:17 | , they'll ask you what songs did record? They will say. I |
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| 35:21 | know. I think it was in . Let's see why it wasn't. |
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| 35:25 | you morphological studies show is the morphology the self, show us the location |
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| 35:31 | that's still not going to be rough us the cellular markers and that's still |
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| 35:36 | going to be enough. Show us action potential firing. And so all |
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| 35:42 | these features the location of the They didn't really more flowers. The |
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| 35:48 | projections targeting different areas of forever or . They're all very important, distinguishing |
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| 35:54 | different subtypes of cells. But ultimately also want to see whether they react |
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| 35:58 | the stimulus in a different manner. are the two cells that have been |
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| 36:03 | using the infrared contrast microscopy. These two micro electrodes cell on the left |
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| 36:09 | another cell on the right when the stimulus. This is the increasing stimulus |
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| 36:15 | here, deep polarization, greater deep , even more deep polarization when a |
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| 36:21 | was passed through the electrode and the was equivalent. Everything was the same |
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| 36:26 | electrode on the left and electrode on right. The difference was the two |
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| 36:30 | cells. They appear different morphological and they treated the same way they were |
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| 36:36 | the same stimulus, the cell on left produced a very fast train of |
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| 36:42 | spikes and these spikes are action potentials the cell on the right produced a |
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| 36:49 | slower spiking activity and much slower frequency the actions of. So the cell |
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| 36:58 | the left reacted to strong stimulus with a sequence like this continuously and the |
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| 37:07 | on the right produced this sequence. now I knew that I'm recording from |
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| 37:17 | different cells but I knew that I publish this paper. So during the |
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| 37:22 | there is another die that's called bios that is inside the electrodes and from |
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| 37:29 | the electrode that die runs into the with your recording and gets taken up |
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| 37:35 | the specifically by the south that you with the selective. And so I |
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| 37:42 | what I had to do after the , I knew what regional hippocampus I |
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| 37:47 | in the cells had a specific firing . So I already knew that the |
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| 37:51 | on the left is an interneuron. cell on the right is a phenomenal |
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| 37:55 | . And then I reconstructed in another I reconstructed a similar subset of cells |
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| 38:03 | are recorded. And so I drew anatomy of the south inspired by Ramona |
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| 38:08 | house work. I used a technique neural loosen up which is a mirror |
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| 38:15 | that ramon alcohol used was was called lucida neural lucid as computer projected mirror |
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| 38:24 | . But we still have to draw cells and reconstruct them. And so |
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| 38:28 | I reconstructed the cell on the left had its selma and the orient slayer |
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| 38:33 | going horizontally and axle on going all way to the applicable regions of parameter |
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| 38:39 | . And when I reconstructed the cell the right it showed a classical |
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| 38:43 | Cell morphology with optical dendrites and basal . And this axon and wide showed |
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| 38:49 | it's actually exiting out of the circuit the adjacent region of the hippocampus, |
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| 38:55 | , I said okay now I actually that but that was not enough to |
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| 39:00 | the paper because I said that this on the left is oh alarm cell |
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| 39:05 | turns out to be this number seven . And the reviewer said how do |
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| 39:10 | know exactly what you're recording from all himself? So I had to cross |
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| 39:16 | with specific cellular markers and one of specific markers that alarm cells express alarm |
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| 39:23 | here number seven X. Process. called Samata status and it also contained |
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| 39:30 | di neurobiology. So I told the well, guess what I recorded from |
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| 39:35 | cell that contains Samantha statin and it the neurobiology and I reconstructed it. |
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| 39:40 | number 7 11 style. The reviewer you got it, you got that |
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| 39:44 | seven cell and now you reported their and now you can study there |
|
| 39:49 | understand what it is. So this a complicated world. These are complicated |
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| 39:56 | and inevitably you have to use a of experimental techniques to reveal the self |
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| 40:03 | markers. You use immuno history, or immuno histology to reveal no |
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| 40:09 | You will use a die, you're biden or by excitement. Then you |
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| 40:13 | reconstruct the morphology through microscopy and threw drawings. Actually computerized hand drawing and |
|
| 40:21 | course during the experiment you have to a beautiful living brain tissue in vitro |
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| 40:27 | their microscope, perfect conditions, perfect same stimulus to have this electrical activity |
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| 40:35 | you record from himself And this was important. Some of the work that |
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| 40:40 | did using these hippocampal circuits in particular in in my post doctoral years and |
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| 40:47 | my earlier years at U. Of was studying epileptic activity in different subtypes |
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| 40:52 | cells. And so my question was epileptic seizure starts, what's satisfy their |
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| 41:00 | Is a Parameter or Sausage Fire Is that number two inhibitory cell? |
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| 41:05 | it number seven inhibitor itself? I to find out that answer. So |
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| 41:09 | was performing multiple patch clamp recordings in hippocampal and cortical circuits and moderate activity |
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| 41:16 | these experimental epileptic conditions to see which Which synchronize it normally 1st and produce |
|
| 41:26 | . It turned out to be The first south and synchronized were actually |
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| 41:32 | cells and they were trying to stop seizures by firing a lot and when |
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| 41:36 | failed it allowed the parameter cells to and project the signal out off the |
|
| 41:43 | that we were studying. So some this work is published and I'll be |
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| 41:47 | to post some of those articles if interested. Maybe I'll show some of |
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| 41:50 | to you later when we talk about couple of C. Two. |
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| 41:54 | So this is not only in the and that brain circuits are very diverse |
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| 42:01 | you have diversity of electrical behaviors of cortical neurons to so this is a |
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| 42:07 | cortex which is a six layer And you can see that if you |
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| 42:11 | an electrode into one of these neurons that you identify more theologically and you |
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| 42:16 | subsequent electro physiological recordings. And then have to prove to the reviewers which |
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| 42:22 | you really which sell you really stuff we reported from. So you do |
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| 42:26 | of the studies that we have already about. Once you do that uh |
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| 42:33 | you can publish stating that you recorded a specific subtype from the mirror. |
|
| 42:38 | when you do electro physiological recordings this a small patch of the cortex and |
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| 42:42 | pluck collected this cell. This cell example will produce a specific sequence of |
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| 42:48 | potentials. It's called stuttering. So hmm. Other cells will have a |
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| 42:59 | signal. So you have an input in silence. And then the uniform |
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| 43:07 | other cells are bursting. So you a continuous stimulus. All of these |
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| 43:13 | are receiving the same stimulus but they're to that stimulus different. This cell |
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| 43:17 | called the bursting cell so it will to the stimulus like with deep |
|
| 43:25 | Mm hmm mm hmm. And some the South will be firing very fast |
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| 43:35 | of action potentials. You can see very fast and some of the cells |
|
| 43:38 | be firing slower frequencies of action So what we're talking about here is |
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| 43:44 | you have a diversity of dialects. these different electrical behaviors is like these |
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| 43:51 | and especially inhibit their into neurons. is where the diversity comes from. |
|
| 43:55 | the fact that the brain is capable producing multiple complex rhythms and we're capable |
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| 44:01 | so many complex multiple computations of different and frequencies is because of the variety |
|
| 44:08 | inhibitory cells and because of their ability speak this language within their own |
|
| 44:14 | So the words are the same action is the same, but they are |
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| 44:18 | differently. They're structured differently and they a slightly different things. It was |
|
| 44:23 | different understanding for these neuronal surface. this is the collective electric behavior of |
|
| 44:30 | , cortical neurons and most of the in this electrical and most of the |
|
| 44:38 | . And the circuits comes from the cell subtypes controlling locally as local into |
|
| 44:45 | , the activity of the projection long excitatory cells. So to perform these |
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| 44:51 | of experiments, you would place a underneath a microscope projecting to the infrared |
|
| 44:58 | , try to stop as many electrodes the lands the slice of the brain |
|
| 45:04 | is sitting underneath the objective here is supplied with cerebrospinal fluid and oxygen. |
|
| 45:09 | it is being fooled as if it's sitting in the animal's brain. But |
|
| 45:13 | now is just about 300 micrometers thick And those slices and neurons and circuits |
|
| 45:19 | and stay alive for about 12 hours the microscope when the conditions arrived and |
|
| 45:24 | the neurosurgeon is great. So you to imagine take a tiny mouse brain |
|
| 45:30 | developing miles brain, right brain which just a centimeter And make a 300 |
|
| 45:37 | slides from a specific brain regions such Hippocampus which is just a couple of |
|
| 45:43 | in the developing small rodent brain. you start with many electrodes and you |
|
| 45:48 | to be a little bit crazy like to do these recordings. These micro |
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| 45:53 | are connected to the pre amplifiers that connected to amplifiers that are computer controlled |
|
| 46:00 | record very fast activity from these and sophisticated and expensive. And then at |
|
| 46:06 | point you run out of the tools it's nine o'clock P. M. |
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| 46:10 | the lab and you find that 10 you say this is gonna be my |
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| 46:14 | electorate holder, it's perfect, it's , it works. Really blew |
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| 46:19 | I'm gonna tape it, I'm going finish the experiment and then your home |
|
| 46:22 | so this is what you do. get creative when you get good you |
|
| 46:26 | the circuits you're swimming in like fish all of this electro physiological setups and |
|
| 46:33 | from theory to practice to experiments. really cool because you can improvise and |
|
| 46:40 | things go wrong, you know cheap like pants serve just as well as |
|
| 46:45 | micro electrode holders. Okay this kind finishes our talk about some of the |
|
| 46:51 | features of neurons but this is not end of talking about neurons and we |
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| 46:56 | not stop talking about neurons and we not stop talking about Julia throughout this |
|
| 47:01 | . And so the last 15 I will spend talking about glia today |
|
| 47:07 | for a long time leah would start just serve supporting functions in the |
|
| 47:11 | So like glue blue like a dough the chocolate chip cookie support and insulate |
|
| 47:19 | . They sure do that. But are also scavengers and they're involved in |
|
| 47:23 | repair and cleanup particular micro glial Micro glial cells are the most mobile |
|
| 47:30 | in the brain to so when there a damage and there is a need |
|
| 47:33 | repair the microbial cells will get This is one of the clips actually |
|
| 47:40 | I have linked here. This is glial cell. I will walk you |
|
| 47:48 | this video in the middle. What is there is an injury that gets |
|
| 47:54 | in the middle here and by the . And plus supporting lecture documents are |
|
| 47:58 | a description of this video of this . So you can read about it |
|
| 48:02 | greater detail and these, all of cells that are labeled here in the |
|
| 48:09 | so all of the cells that are here in white are labeled with specific |
|
| 48:14 | wheel stay for a specific label from leo and this white dot in the |
|
| 48:22 | is the site of injury. And you're seeing is that injury happens and |
|
| 48:29 | following the injury you have mobilization of cells and they start extending their processes |
|
| 48:38 | they're actually beyond just extending their processes the area where there's damage so that |
|
| 48:44 | can clean up debris and do the , they actually physically start moving into |
|
| 48:50 | space through the brain. So Michael we all saw some of the most |
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| 48:56 | cells in the brain as the injury you can see the process is rushing |
|
| 49:05 | . It's just 10 micro meter This is happening over minutes and then |
|
| 49:11 | have a slow migration of the so forward the area where the injury has |
|
| 49:17 | place and it will just replay this more time. There's the injury, |
|
| 49:22 | processes extending and then microbial moving in take care of that thing. |
|
| 49:29 | okay. So why could we ourselves incredibly important? Ah And it's not |
|
| 49:40 | that Michael glial cells are also involved inflammation regulation through molecules that you will |
|
| 49:48 | hearing and having hearings. And covid come about, cytokine and cytokine storms |
|
| 49:55 | inflammatory molecules released. So inflammation is reaction to an injury and controlled release |
|
| 50:03 | inflammatory, pro inflammatory Marcus mobilizes the response and mobilizes to clean up and |
|
| 50:10 | the brain following the injury. uncontrolled release, uncontrolled storms, they're |
|
| 50:19 | on the side of fines rather than calm. Release of side of fines |
|
| 50:24 | be detrimental and can offset the So, Michael Birbiglia is very intricately |
|
| 50:30 | in this process of regulation of Kind storms astra sizes another subtype of |
|
| 50:39 | cells on this slide very nicely summarizes cells that we're talking about. So |
|
| 50:45 | is the micro glial cell. What talked about this is a straight sides |
|
| 50:50 | astra sides have multiple different functions in brain. Astra sides are part of |
|
| 50:56 | we call a tripartite synapse. So the two neurons are communicating, the |
|
| 51:02 | acidic processes are wrapped around the synapses the two neurons, constituting the third |
|
| 51:08 | the tribe of the synapse by with two neurons and try you have one |
|
| 51:14 | communicating to another neuron and glia in . Astro science is very intricately involved |
|
| 51:21 | lot of Francis's household chores, household is regulating glutamate and amount of glutamate |
|
| 51:29 | incredibly important. So neurotransmitter regulating the of neurotransmitter. There's local increases in |
|
| 51:36 | such as potassium astrocytes will slurp it , siphon it off and send it |
|
| 51:42 | distributed throughout the extra city uh processes the interconnected astro sitting Metformin. It |
|
| 51:51 | synaptic transmission. It's involved in synaptic , what is called sin Opto |
|
| 51:57 | The birth of the synopsis and it involved in synaptic plasticity, wow extra |
|
| 52:03 | are really important and that's not all Rasyid and feed also sit on top |
|
| 52:08 | the capillaries and we talked about the brain barrier. He said that there |
|
| 52:12 | this barrier between the blood and the and this barrier is showed right |
|
| 52:19 | This is the blood vessels right And of course you have the end |
|
| 52:22 | the filial cells comprising the walls of blood vessels. You have the parasite |
|
| 52:27 | here and the blood vessel cells or thai junctions. So things cannot pass |
|
| 52:32 | these tight junctions. So this isn't and now surrounding in the brain at |
|
| 52:38 | blood brain barrier, you have the glial processes here and feet of astro |
|
| 52:43 | processes. And what it tells you is that only the things that are |
|
| 52:50 | enough to faster the blood brain barrier tai junctions or their soluble, that's |
|
| 52:55 | you will. They can pass through membranes can enter into the brain or |
|
| 52:59 | they have specific transporters or something that their transport across the walls, other |
|
| 53:11 | and entering into the brain. So is a barrier here. And that |
|
| 53:16 | is very important. So that things are in the body kind of freely |
|
| 53:19 | into the brain. Everything that's in blood doesn't always cross into the |
|
| 53:24 | That's what we talked about where Renea when you have a viral load in |
|
| 53:28 | blood, It doesn't mean it's going enter into your brain. But if |
|
| 53:32 | viral load in the blood from something COVID-19 becomes very heavy and you have |
|
| 53:39 | and inflammatory processes, there's going to a breach off the blood brain barrier |
|
| 53:45 | the tight junctions of the information and of the cells that are involved in |
|
| 53:52 | the blood brain barrier and the passage the mall. So that's when you |
|
| 53:56 | a breach and that's when the infectious and other molecules can enter into the |
|
| 54:03 | . Meningitis due for example can enter the brain like that viral bacteria enter |
|
| 54:09 | the brain like that too. Not viruses and other things. And toxicants |
|
| 54:14 | uh poisons can also enter into the through breached blood brain barrier. The |
|
| 54:20 | brain barrier is very important. Blood barrier is also it's an obstacle to |
|
| 54:26 | lot of the pharmacological treatments of the . So as we develop very slowly |
|
| 54:32 | clinical definitions we have to understand that take most of the drugs on the |
|
| 54:40 | , not you but most of the on the market are in what form |
|
| 54:44 | shape in the form of a pill a tablet. What happens to the |
|
| 54:51 | and tablet when you put it on tongue and go straight into your |
|
| 54:55 | No you swallow it. Part of gets digested. How did it get |
|
| 55:02 | ? Alright I'm gonna get some more then the fraction of it enters through |
|
| 55:06 | digestive system into your systems and systematic flow. So you have a fraction |
|
| 55:13 | the drug that you have taken that have swallowed it is now in the |
|
| 55:17 | . And if you're targeting the brain disorder of brain disorder now you have |
|
| 55:23 | problem because you have to have a of the drug to limit systemically because |
|
| 55:29 | have the blood brain barrier in order that drug to actually pass through the |
|
| 55:34 | brain barrier and have a significant effect the brain. So it presents challenges |
|
| 55:42 | brain barrier protects us. But from perspective, blood brain barrier is a |
|
| 55:48 | . And so from neuro pharmacology perspective drug design perspective, you have to |
|
| 55:53 | about small molecules. If you're targeting brain through systemic injection of a drug |
|
| 56:00 | pharmaceutical, you have to think about molecules molecules that passed through blood brain |
|
| 56:04 | . Maybe there's transporters, maybe it's that can facilitate of those molecules and |
|
| 56:09 | you want to have molecules that not pass into the brain but are taken |
|
| 56:15 | and treat specific cell subtypes that we about inhibitory excited or maybe even specific |
|
| 56:21 | of the inhibitory cells period. And when you hear sometimes commercials on |
|
| 56:28 | let's say a treatment of depression, can be a neurological clinical depression or |
|
| 56:37 | anxiety and you hear commercials and say if you're taking this drug from |
|
| 56:43 | the new experience all these other And then there's these commercials of naming |
|
| 56:51 | have in incontinence, if you had or the opposite, if you have |
|
| 56:58 | or suicidal thoughts or if uh your abilities are imperative, like wow, |
|
| 57:08 | what's going on, why there's so side effects from some of the drugs |
|
| 57:13 | you're taking systematically because once the drug in the system that's gonna bind to |
|
| 57:19 | of these molecules and proteins you can these proteins FM RP in the brain |
|
| 57:23 | example. But you can have FM and other organs. So it's |
|
| 57:28 | It's very complicated. Right? And it's systematic ingestion of the drug that |
|
| 57:34 | specific brain abnormality in the end and significant side effects from the whole |
|
| 57:41 | Because you have to have so much of that drug in the system in |
|
| 57:44 | blood so that a fraction of it passes into the brain. Has the |
|
| 57:49 | needed desire for design defect for it control a specific brain abnormalities. Okay |
|
| 57:59 | we also have these uh illegal deandra and illegal Denver sides form myelin around |
|
| 58:08 | . So in the cns it's illegal sides and you can see that the |
|
| 58:11 | Denver sides have multiple processes and each of the processes becomes a single myelin |
|
| 58:20 | along with this violin ated axons that will see in the CMS. |
|
| 58:26 | The barrier you have a pen dermal append them all cells control the separate |
|
| 58:31 | control the passengers cerebrospinal fluid. Also to suspected to be potentially stem cells |
|
| 58:41 | can turn later into either the glial or into neurons. So they have |
|
| 58:49 | interesting functions here. The other cell cell that I talked about here is |
|
| 58:56 | glial cells, radial glial cells are important for migration. An outgrowth of |
|
| 59:03 | processes and radial glial cells and neuronal and glial precursors. So that |
|
| 59:11 | that during early development these radio real will be guiding the migration of neurons |
|
| 59:17 | the algorithm processes and the final location neurons in the specific circuits. And |
|
| 59:23 | they came orphan to become neurons and cells themselves. So wait a |
|
| 59:29 | What does that mean, migrate? migrate. Indeed neurons migrate. This |
|
| 59:34 | another supporting lecture material link that I for you. This is radial glial |
|
| 59:42 | . Radial glial cells serves sort of a lattice or road and this neuron |
|
| 59:49 | along that road. So during early neurons are formed in certain parts of |
|
| 59:54 | brain where new neurons are born and neurons migrate to find their final destination |
|
| 60:01 | the brain, inside the circuit beat the cortex or the hippocampus layer three |
|
| 60:08 | layer and so on. So there's cytoplasmic continuity that forms between radio glial |
|
| 60:14 | and neurons here and allow for these to use radio glial processes is the |
|
| 60:21 | to find their final destinations in the . This is chain migration of neurons |
|
| 60:30 | you can see how there is a complex migration activity. This is in |
|
| 60:36 | but you will see this kind of migration activity going on in the viva |
|
| 60:41 | course and you can see again in number of neurons here they become cytoplasm |
|
| 60:47 | continues during early development and they're traveling these process system lattice system establishing the |
|
| 60:55 | mature circuits and more precise circuits that will find in the adult brain. |
|
| 61:01 | , radial glial cells and and very for this migration process out there. |
|
| 61:06 | very important for the development. Well release growth factors and those growth factors |
|
| 61:13 | very important for the growth outgrowth of development of the synapses during early |
|
| 61:20 | But the growth factors can also be growth factors that influence your growth as |
|
| 61:26 | too. But astrocytes and blood brain . And the point to take home |
|
| 61:34 | point is that we are not we are actively involved in synapse formation |
|
| 61:42 | function in synaptic plasticity. Battaglia do produce action. They do not produce |
|
| 61:50 | fast fluctuations that neurons produce called action . Instead they communicate by producing these |
|
| 61:57 | lower calcium waves that travel across a sides and across the interconnected astra acidic |
|
| 62:06 | . So this will conclude our lecture because when we come back we will |
|
| 62:12 | about another disorder and two of them that are related to myelin dysfunction. |
|
| 62:19 | talk about Charcot Marie tooth disease and talk about multiple sclerosis. And so |
|
| 62:26 | you go. We're gonna have to another page from Ireland dysfunctions and write |
|
| 62:31 | more information and more clinically relevant information what causes multiple sclerosis um or causes |
|
| 62:39 | marry tude disease. But for today concludes our overview of the major subtypes |
|
| 62:45 | the glial cells. Microglia exercise. little undersized defendable cells, radial glial |
|
| 62:52 | and the videos that you can find electric supporting materials as well. So |
|
| 62:57 | a great weekend, everyone and I see you next lecture in person in |
|
| 63:05 | from stopping the recording |
|
