| 00:02 | So this is lecture three of Cellular Neuroscience. But we're going to |
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| 00:09 | talking about some of the neuronal classification some of the newer methods that are |
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| 00:15 | introduced and how to classify neurons. as you may have looked at those |
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| 00:22 | , uh or in general, if thought about this is that as I |
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| 00:29 | , the the gold standard for how subclass neurons, is it moving |
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| 00:35 | Because the technologies are improving, there's lot more sophisticated molecular techniques that get |
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| 00:43 | and they become an important part of classification of subtyping of neurons. Uh |
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| 00:51 | , what we had for quite a is we had the ability to visualize |
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| 00:57 | morphology. We had the ability to action potentials and even cross stain the |
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| 01:07 | that we report from or the cells are of interest for us with specific |
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| 01:13 | markers. So in the nineties and to 2010, this is kind of |
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| 01:22 | gold standard. And if during the , you can sample part of the |
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| 01:31 | that you're recording from physically by essentially its cytoplasm into the pipette, then |
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| 01:39 | were able to do a single cell . A sequencing works out. But |
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| 01:47 | a single cell. And we talked the fact that these recordings, these |
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| 01:51 | of recordings, electrophysiological recordings from one multiple cells are painstaking. They're |
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| 02:01 | they're time consuming. And if you an ace, you could potentially draw |
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| 02:10 | from maybe 20 cells a day. you would be just regarded like, |
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| 02:15 | , it can work fast and do lot of very, be very |
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| 02:19 | So now we've spent quite a bit time talking about this slide and this |
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| 02:26 | the area in the hippocampus. And point of this slide was that we |
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| 02:32 | a lot of diversity in the inhibitor neurons. And if you recall the |
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| 02:38 | into neurons for the most part, release their inhibitor and their interneurons, |
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| 02:44 | release neurotransmitter gamma. So we talked the types of cells that you can |
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| 02:51 | projection cells and projection cells are thought being excitatory cells and they're typically the |
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| 03:01 | shake cells that release glutamate. So if you have an excitatory synapse |
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| 03:10 | you have a neuron that produces this glutamate is going to be located |
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| 03:21 | the vesicles. Here is the soul the neuron and this is referred to |
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| 03:29 | presynaptic. It's presynaptic because this is the circular fusion takes place. And |
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| 03:38 | gets released into the synaptic cleft. can lower this, I think I |
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| 03:44 | so that it's released into the synoptic . So this is an excitatory, |
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| 03:51 | typically projection cell. Now it will contact like we saw, for |
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| 03:58 | a synaptic dendrites. And so this another cell and contact postsynaptic gun drives |
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| 04:07 | little spines here and release this neurotransmitter postsynaptic. So this is now called |
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| 04:15 | synaptic this side side, it's it's posy neuron. Here, it |
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| 04:25 | its own synapse, it has its axon and and it turns out that |
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| 04:34 | is a different type of vesicles and neuron releases gaba. So typically these |
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| 04:43 | inhibitory neurons, they come in many shapes and they are referred to as |
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| 04:56 | because they stay within the local So we see that here we have |
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| 05:01 | inhibitor into neurons at least 21 different subtypes is defined by their location. |
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| 05:07 | within these three layers, the dendritic and projections and axonal projections and synopsis |
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| 05:17 | they're being formed in these cells. in addition to specific cell markers, |
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| 05:22 | these different subtypes of inhibitor interneurons stain express such as basket PV CCK. |
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| 05:31 | are different reval and CCK. Polycystic and these are different molecules. So |
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| 05:36 | different genetic expression that's how they're different . And so then molecular part of |
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| 05:44 | story becomes quite important and this is molecular signature of these five cells, |
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| 05:55 | and this is 123, 12345 is signature of five of these cells. |
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| 06:05 | this is done with the single cell a sequence, sorry. And instead |
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| 06:12 | just doing it on a single what can be done is these techniques |
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| 06:18 | you will hear that are important, you may hear it within the context |
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| 06:25 | drug discovery but anything that is high . But OK, so what does |
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| 06:42 | mean? That means that you can a high volume or something of |
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| 06:47 | you can study a lot of a high volume of cells. |
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| 06:53 | you can study many brains in a period of time. And drug discovery |
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| 06:58 | , a lot of molecules can be on the tissue and the higher |
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| 07:04 | uh the models of the systems, easier those models are, the quicker |
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| 07:10 | can get to the answer. So example, you suspect that 2000 compounds |
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| 07:16 | a particular type may be useful in inflammation. So if you did one |
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| 07:23 | for each student in each post doc , that would take you 100 |
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| 07:28 | And we still need just be a of the way done. Uh If |
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| 07:33 | did it one by one cell and trying to look at each drug |
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| 07:38 | some model that it takes a long . So instead you speed that process |
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| 07:43 | . And here we have these sorts we talked about. So you can |
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| 07:48 | the tissue that you can uh uh a particular uh side of the |
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| 07:53 | Let's say you want to isolate the and then you're gonna homogenize the |
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| 07:58 | You're gonna put it through these microfluidics have barcoded beads that will tag on |
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| 08:05 | the cells here with the beads and droplets or are pooled for synthetic DNA |
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| 08:11 | C DNA synthesis, amplification and So instead of just this one RN |
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| 08:19 | extraction draw from a single cell. you're talking about pumping hundreds of |
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| 08:25 | thousands of cells today, potentially through system. And what it allows you |
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| 08:30 | do, it allows you to determine molecular profile just like we saw previously |
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| 08:37 | the molecular profile of different subtypes of . Now, this is where it |
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| 08:46 | kind of a tricky. OK. this is where if it is difficult |
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| 08:56 | follow, as I would say that can together look at that figure legend |
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| 09:03 | we call a lot of my alternative descriptions will contain full figure legends for |
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| 09:11 | figure shown at will be abbreviations. that's because I either didn't finish or |
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| 09:16 | want you to go into the supplemental material to actually drag out that figure |
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| 09:23 | . This is interesting, this is multiplex fluorescence in situ Hah fish for |
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| 09:32 | China. And what it is is it has a single and double label |
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| 09:43 | to allow tens to hundreds of Mrnas be co acid in individual cells within |
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| 09:50 | sections. It's so the figure legend pretty long and there's a lot of |
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| 09:56 | uh details in that description, I you to read it on your |
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| 10:01 | but essentially it allows to tag like talked about many uh messengers and creates |
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| 10:12 | of this 0101, almost a binary of fluorescence then can be that can |
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| 10:19 | read. Yeah, what else do have? So those that have taken |
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| 10:28 | neuroscience course are familiar with this retinal . If you have taken anatomy or |
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| 10:34 | or neurobiology, you probably also covered retinal circuit, the retinal circuit is |
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| 10:40 | of. And when we talk about retinal circuit, we're talking about where |
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| 10:45 | processing of white face fled. So the light comes in and travels through |
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| 10:53 | eyeball, it actually activates photo receptors the very back of the record. |
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| 10:59 | we have rod photoreceptors that are elongated and we have cone like cone shaped |
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| 11:08 | receptors. So, raw photoreceptors are vision or gray scale co for photoreceptors |
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| 11:16 | color uh process. Now, these , they will convert the energy of |
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| 11:25 | the photons into electrochemical signal and they communicate this information from photoreceptors to the |
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| 11:34 | cells. And this will occur in following figure where we talk about B |
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| 11:41 | as they bipolar cells. And then have these bipolar cells that connect onto |
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| 11:50 | ganglion cells and the axons of these ganglion cells, they form the optic |
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| 12:00 | . So they're responsible for putting that from the retina into the higher order |
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| 12:08 | information processing centers into the thalamus OK. So in addition to those |
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| 12:18 | three cell types, we also have horizontal and amari cells. But for |
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| 12:25 | purposes, uh we're gonna move on the next figure that describes class classification |
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| 12:36 | retinal bipolar cells. In this retinal bipolar cells, B CS. |
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| 12:43 | it looks sort of a like interesting of how can we distinguish between different |
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| 12:53 | , other different subtypes of bipolar cells these B CS? Because uh when |
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| 13:01 | took neurobiology or my neuroscience, which said bipolar cell, we didn't say |
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| 13:05 | there's many different subtypes, how many subtypes? So there are multiple methods |
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| 13:14 | you can use. And in this is you know sets of high |
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| 13:19 | data, namely morphological electron microscopic reconstructions . So when you're talking about |
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| 13:30 | we're talking about morphology when it says calcium imaging. Uh do you guys |
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| 13:41 | what calcium imaging is or physiological calcium is? Ok. Let me review |
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| 13:49 | . So you have cells and these are sitting in the tissue here and |
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| 13:59 | these cells get active, the calcium inside these cells, they increase. |
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| 14:08 | this indicates active cells. If the levels are going up, if the |
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| 14:16 | levels are not changing or if they're , the cell is less active, |
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| 14:24 | never say it's inactive because so less . So that's just the basic principle |
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| 14:35 | , of physiology, the cells that essentially and in intracellular calcium concentrations is |
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| 14:44 | good indicator of neuronal activity. It not the electrical activity, it is |
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| 14:54 | concentration measurement of calcium, but it very well. And in many |
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| 15:02 | almost identically correlated to changes in So calcium levels goes up. That |
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| 15:10 | the cells are more active. So you can observe which cells are more |
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| 15:17 | and which cells are less active. would you observe that? And how |
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| 15:25 | you image calcium? So you have put something on this tissue and you |
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| 15:32 | something in this tissue that binds calcium makes this calcium light up so many |
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| 15:40 | dyes that you can visualize calcium, sensitive dyes calcium, there's several different |
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| 15:50 | . So when this lights up, you can do is you have the |
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| 15:59 | objectives and I could see the bigger that you can shine the light on |
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| 16:07 | tissue and you can measure the amount calcium. Ok. So you're imaging |
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| 16:14 | amount of calcium light that is coming from different regions of this tissue. |
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| 16:21 | collecting this into a microscope and you're it on some digital screen that shows |
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| 16:29 | the calcium active cells like this or example, traces. So this is |
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| 16:35 | lot of calcium, it just transforms into a trace. It's not an |
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| 16:39 | trace, it's a digital trace or this cell, maybe it's a little |
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| 16:44 | in this. So now we we track acidity of of calcium. And |
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| 16:52 | of reporting action p which we talked in the previous lecture today. |
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| 16:59 | this is an alternative way and there's other ways in which we can track |
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| 17:04 | of neurons. But calcium imaging or sensitive dyes is one way in which |
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| 17:10 | can track neuronal activity. And we'll back and talk about that briefly when |
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| 17:14 | have lecture of neuronal imaging. But least that places in you within what |
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| 17:21 | meant by physiological calcium imaging, it's because it's activity, it's changing and |
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| 17:27 | correlated concentrations are correlated to the actual . And uh neuronal potentials and molecular |
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| 17:38 | are basically drops and into the following types, one type of rod BC |
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| 17:45 | bipolar cell and 14 types of cone cells. So that's a lot |
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| 17:53 | We're talking about 15 different sub vibes the bipolar cells and it's further subdivided |
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| 18:03 | eight on and six off types of cells. So how do you, |
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| 18:10 | do you analyze something like this? difficult if you don't know the matter |
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| 18:17 | while the statistical models don't have access math works or math lab, you |
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| 18:23 | need to go to department of mathematics get some help from your peers |
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| 18:28 | or some mentors. But there are ways. In this case, it's |
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| 18:32 | T distributors stochastic neighbor embedding plot showing clustering of 20,000 bipolar cells that were |
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| 18:43 | by fluorescence activated cell sorting from visual . But they are expressing this fluorescent |
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| 18:52 | , green fluorescent protein GFP. It a transgenic mouse line. Wow, |
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| 18:59 | a, that's a mouthful, But the transgenic, it means it |
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| 19:04 | some gene altered, maybe it's a mouse because it actually has calcium indicators |
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| 19:11 | already within the mouse. You don't to apply a dye on the |
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| 19:15 | right. So, and we have uh mule cells as mg profiled by |
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| 19:23 | sequencer. And this uh TSNE which the stochastic neighbor embedding plot provides a |
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| 19:30 | way to display cell clusters is defined high dimensional analysis of correlations in the |
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| 19:36 | expression in two dimensions. So you essentially RN ac, you drag out |
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| 19:43 | of the information about these cells. cell, let's say this cell right |
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| 19:50 | has this molecular profile. This cell here has this molecular program you wanna |
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| 19:57 | now somehow compare the molecular profiles, ones are most similar, right? |
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| 20:05 | is five shown. But we're working with 15 and visually you'll say |
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| 20:08 | of course, this right here is but then this is nothing here. |
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| 20:14 | right here is overlapping here, but missing all of these. But you |
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| 20:18 | get a little bit more mathematical with , more quantitative. So you would |
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| 20:22 | uh a model like a stochastic analysis and what it does, it produces |
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| 20:27 | clouds. And you have essentially the neighbor embedding in two dimensions and you're |
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| 20:38 | how similar are the genetic uh are uh profiles, molecular profiles. So |
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| 20:47 | more similar they are they get clustered the same cloud. So these are |
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| 20:54 | DC 7th 7th subs, this is new and Leal CBC 38. Then |
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| 21:03 | other thing that this plot shows is proximity. So the closer the two |
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| 21:10 | are to each other, that means more molecular overlap exists between them. |
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| 21:17 | further apart they are, that means less of that molecular similarity or overlap |
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| 21:25 | the expression. So then you create a Denro graph just like the dendrites |
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| 21:35 | and spreads. These are referred to Denro grams. So you have relationship |
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| 21:41 | BC cell types are shown in the of Denro gram that was created based |
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| 21:45 | their transcript to similarity. So this the tend ground that gets created from |
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| 21:52 | analysis. And then c the sketches the 15 BC types whose terminal branches |
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| 21:58 | axons are located in different subliminal sublimate the inter flexor layer of the retina |
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| 22:05 | the retina. So you still need but it's interesting that these clouds that |
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| 22:12 | the cells based on their molecular those subtypes of molecularly profiled cells, |
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| 22:20 | can be described as having unique and somewhat similar morphology. And then in |
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| 22:30 | cases, morphologically what is really different this and this BC seven BC |
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| 22:37 | So if you use just the even if you used calcium imaging on |
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| 22:43 | of that physiology, even if you action potentials and they fired the same |
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| 22:50 | the molecular analysis may in fact show VC six and BC seven belong to |
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| 22:57 | different molecular clouds. So, but , it complicates things a little |
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| 23:05 | but it also helps us a lot , with subtyping and thinking about neuronal |
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| 23:11 | from molecular transcriptome perspective. Um And cool. Yes. Are there |
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| 23:23 | Yeah. Good question. The last on the exam, let's think about |
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| 23:34 | . I, I don't know, missed something. Did you find a |
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| 23:39 | in the paper? They're not all here, for example, BC |
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| 23:55 | Yeah, I know. I was say if it's not explained in the |
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| 24:01 | , it could be a typo and may be the first person that caught |
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| 24:06 | and I went through like five reviewers like two months. Nobody saw |
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| 24:09 | I don't know, I don't That's, that might not be |
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| 24:12 | So yeah, it's this, it's measure basically it's a, a stochastic |
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| 24:23 | is described here that it's a distributed T distribution of stochastic neighbor embedding them |
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| 24:31 | . So it, it's compares, guess using statisticss, how similar are |
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| 24:37 | uh molecular expressions and then assigns them these, the stochastic model assigns them |
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| 24:43 | these plots. It's not to say that's the best model. Somebody may |
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| 24:49 | a different model and you know, of H University versus Rice University and |
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| 24:55 | they may get uh instead of 15 they may find 20 clouds. |
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| 25:01 | So it's, it's a little, a little bit of a always a |
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| 25:05 | bit of built in bias and in model and analysis because any model and |
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| 25:11 | relies on certain variables. So, in this case, the variables are |
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| 25:18 | analysis. So you probably trust it well. But if you change |
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| 25:22 | so you reanalyze all of these there might be slight differences. So |
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| 25:26 | all about the size of the If it's statistically significant, then you're |
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| 25:35 | . All right. So example of we are talking about is synoptic |
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| 25:43 | So we've talked about OK, what different about different sometimes. No, |
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| 25:51 | understand this neocortical neurons. This self classification that we talked about glutamic glutamate |
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| 26:01 | gaba morphological distinction of cells like a and molecular problem. Um It's also |
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| 26:12 | important to have the full morphology of cells. And you can describe this |
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| 26:19 | morphology using labeling techniques, using viral , um using some transgenic animals. |
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| 26:28 | you can light up the cells so can see their branches in vivo and |
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| 26:33 | they uh uh and the full morphology it both in vitro and vivo. |
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| 26:39 | you have different cells, sometimes what really interested in is how these cells |
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| 26:45 | connected to each other. So the of how the cell communicates to another |
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| 26:51 | is electrophysiological reporting. You can kind uh rely on calcium a little bit |
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| 26:57 | it's not that great of an imaging for cell to cell connectivity because if |
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| 27:05 | L lights up and another one lights calcium and imaging may have some temporal |
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| 27:12 | and analysis that are built in, you don't have an electrophysiology. So |
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| 27:17 | best way to see connectivity between cells still using electrophysiological recordings or transsynaptic viral |
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| 27:28 | . What does that mean? That that you again expose the tissue or |
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| 27:35 | somehow virus in the tissue. And virus is capable of jumping from one |
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| 27:42 | from one cell through the synapse into interconnected cell. And because it has |
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| 27:50 | visual tag, you can trace which or which processes are connected to to |
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| 27:58 | other processes, then you have some synoptic configuration. So if you worked |
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| 28:05 | sort of about the rock connectivity, cell is connected to these three |
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| 28:10 | This one is connected just to these two are just talking back and |
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| 28:14 | to each other. You want to where the somatic contacts are formed. |
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| 28:19 | that still is relevant. So when talking about the hippocampus, where the |
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| 28:23 | are coming in, that is still to understand the whole configuration of the |
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| 28:29 | . So now from the cells, building a network where they formed on |
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| 28:33 | Somas and the dendrites and the Ridic , which projections are long range |
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| 28:40 | That's when we talk about projection cells which projections and which synapses are localized |
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| 28:47 | the network. And then finally, have this synaptic reconfiguration. And what |
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| 28:55 | means is that this connectivity is It can be changed and it changes |
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| 29:02 | lot, especially during early development and can change a lot through a process |
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| 29:09 | learning. So the cellular mechanisms that , for example, learning and |
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| 29:15 | Some of the cellular mechanisms are that Synopsis, OK. The synopsis that |
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| 29:22 | active and the synapses that are active cell one, these are newly formed |
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| 29:29 | . This is active synapse here and synapse here is maintained. But the |
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| 29:36 | in dash lines here, this neuron not very active talking to this |
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| 29:42 | And what happens is this synapse because two neurons don't communicate with each other |
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| 29:48 | well. And therefore this doesn't communicate the third one. Both of these |
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| 29:53 | can get eliminated. And this happens lot during the early development where we |
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| 30:00 | have more connections at the beginning in brains than we end up as |
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| 30:07 | A lot of things are non specifically in these neuronal networks. And these |
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| 30:15 | that are not active, they get or all pruned, they get |
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| 30:20 | essentially the connections that are active, strengthened, the same applies during the |
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| 30:28 | of learning and memory. So we'll two lectures on plasticity and learning and |
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| 30:34 | and the rules by which neurons strengthen synopsis or eliminate the synopsis. And |
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| 30:43 | this is really the connectivity configuration of connectivity. And the fact that is |
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| 30:49 | plastic process. So you can have . And even in adult brains, |
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| 30:55 | have plasticity, we can still we can still forget things. |
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| 30:59 | we still have a significant amount of going on, but not as much |
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| 31:05 | during early development and childhood into early . So eventually and for some people |
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| 31:17 | these cells and these networks and connectivity how cells communicate to each other might |
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| 31:24 | very useful for engineering tissue. And what is tissue engineering? It's literally |
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| 31:32 | tissue having the south. This is little like c rainmaker and you essentially |
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| 31:43 | this with cells. OK. You some coating on top, maybe you |
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| 31:49 | to have double layers of two types cells. And an example of that |
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| 31:56 | be a severed nerve in the periphery nerves in the periphery can regrow, |
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| 32:04 | cannot regrow in the cns uh following , but nerves in the periphery can |
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| 32:11 | . But you can also facilitate that process. You can facilitate that regrowth |
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| 32:16 | . For example, creating a little that has similar cells or the same |
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| 32:26 | of cells that create insulation around the . And you can insert it in |
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| 32:34 | area where the axon or where the was broken, surrounding that area to |
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| 32:42 | and promote the regrowth. And of , uh in this uh case, |
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| 32:49 | would be one set of cells and that you're gonna be interested in |
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| 32:55 | And if you are potentially trying to something in the SOMA, it might |
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| 33:00 | another different set of molecules or tissue something like that, either artificial or |
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| 33:10 | tissue that you can apply. So is all at experimental level. Uh |
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| 33:18 | you know, grafting existence surgery, ? You graft things, people take |
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| 33:25 | from different parts of the body and over other parts of the body that's |
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| 33:30 | so that skin from will grow. . But this is a little bit |
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| 33:36 | complex than that. And it's really to look at different self subtypes and |
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| 33:40 | you would tissue engineer, different self , how you would have them interact |
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| 33:45 | each other without and, and have in some way in such a way |
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| 33:49 | it, it, it, it actually promote the formation of that |
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| 33:55 | If you engineer something in the wrong , it could kill those neurons and |
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| 34:01 | , those axons too. So there's lot of work that goes into this |
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| 34:06 | it's an interesting field for me. a very interesting field. All |
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| 34:12 | OK. So are there any questions ? So now we're going to venture |
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| 34:23 | the third uh lecture presentation that you in your modules and now your pages |
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| 34:34 | think are also activated. So we be able to see both as |
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| 34:40 | So let's see. I don't know happened, but I may have not |
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| 34:46 | it correctly. Yeah. Now I'm on the screen and we're going to |
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| 35:02 | about glia and there are many different of gua but not as many as |
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| 35:09 | . Sometimes the major types of radial glia ligo denroy microglia, |
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| 35:18 | those are the four major subtypes and talk about all of them today and |
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| 35:27 | also we'll end up talking about them little bit on Mon Tuesday. |
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| 35:35 | the development of neuronal processes is very . Neurons are born and then they |
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| 35:43 | to their final destinations and they develop of these processes. The dendrites, |
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| 35:48 | dendritic spines, the axons and they that specific connectivity that we were looking |
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| 35:54 | . Some of them become projection cells stay within the locus local circuits. |
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| 36:00 | radio glial cells are very important for migration and guidance. Radial wheel cells |
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| 36:09 | uh are thought as progenitor cells that become other types of real cells or |
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| 36:19 | neurons, oligodendrocytes and shown here, in the CNS are responsible for forming |
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| 36:31 | myelin segments. So one oligodendrocyte will multiple processes or arms extending out and |
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| 36:41 | around and each one of the processes a single myelin segment. So this |
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| 36:49 | again can have 10 can have 100 segments. It depends how long the |
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| 36:55 | is, for example. But each is going to be formed by one |
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| 37:02 | of a ligo underside. The one liga underside can interact with multiple |
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| 37:07 | multiple neurons and multiple axons in the , microglial cells, which are shown |
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| 37:17 | are the smallest and the most mobile , glial cells and the most mobile |
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| 37:25 | in the brain period. They are with injury, clean up and |
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| 37:33 | They're involved in immune response of the and they release cytokines and cytokines |
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| 37:43 | And in general, normal release of means normal care and homeostasis, kind |
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| 37:50 | taking care of things that is things are breaking a little bit all |
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| 37:54 | time, things need to be cleaned just like it every day. Uh |
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| 38:01 | when there is an injury, they activated microglial cells, they rush into |
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| 38:07 | side of injuries, start cleaning up injury, they start releasing cyber con |
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| 38:12 | signals and immun faults. And that important because the injury could be due |
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| 38:19 | an infection break. You have to fight that infection. So, microglia |
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| 38:28 | the cytokine signaling is very much involved control of homeostasis and inflammation, inflammatory |
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| 38:37 | in the brain astrocytes that are shown . You can see that ostracizes have |
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| 38:46 | extensive processes and cover quite a large just for a single cell. And |
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| 38:54 | of these processes wrap around the synopsis . So astrocytes intricately control synapse |
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| 39:03 | which we call synaptogenesis, synaptic which we call communication between the two |
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| 39:12 | when one releases neurotransmitter. And another reacts to it. The one that |
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| 39:17 | the receptor on the boss cell. intricately involved in synaptic transmission snap the |
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| 39:25 | and homeostasis around synopsis of neurotransmitters and and ions that it monitors around neuronal |
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| 39:34 | . But the on the other it, its end speed processes extend |
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| 39:40 | wrap around the micro capillaries in the vessels of the brain. In conjunction |
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| 39:48 | endothelial cells, suicides form what is the blood brain barrier. So they |
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| 39:54 | , there's a lot of things in blood that do not cross into the |
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| 39:58 | . And likewise, there's a lot things in our blood that cross into |
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| 40:01 | brain. And even if they do into the brain, they have to |
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| 40:08 | in a controlled fashion, a certain of things crossing into the brain and |
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| 40:17 | by controlling this. This basically is of the police posts that controls what |
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| 40:23 | from the blood vessels and en cross the brain tissue. So it comprises |
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| 40:29 | blood brain barrier collectively glia control and influenced by growth factors. They control |
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| 40:37 | genesis, they control synaptic transmission, also synaptic plasticity. So configuration and |
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| 40:43 | of the con connect connectivity between the also homeostasis. So homeostasis is just |
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| 40:51 | to a balanced a a and if may a normal, balanced state of |
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| 40:59 | and activity. So these are a glial cells illustrated here and this is |
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| 41:06 | a drawing by Ramonica Hall of different glial C. And what this shows |
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| 41:13 | you click on these videos and we watch them together. But what this |
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| 41:19 | here, this is this this long , this is great we have, |
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| 41:26 | is in no. And when we the uh early formation of the nervous |
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| 41:32 | , the birth of neurons and migration their final destinations. What do they |
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| 41:38 | on? So these ropes serve as highway as a migration highway or as |
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| 41:45 | lattice as the ladder to climb And neurons become cytoplasm or at this |
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| 41:52 | , our cytoplasm continues with rare. so they, they share the same |
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| 42:00 | and they move along this road to their final destination. So that's cell |
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| 42:07 | that it's very important um in guiding neurons into certain areas. As I |
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| 42:14 | , their progenitor cells, some are found in adult brains, although they |
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| 42:20 | very predominantly expressed during early brain formation migration of neurons. Uh and some |
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| 42:30 | migration from one of the zones where form called the sub ventricular zone uh |
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| 42:37 | without radial wheel guide. So there other um cues, chemical cues, |
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| 42:46 | cues, cell and cell recognition The neurons can help guide themselves without |
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| 42:54 | this rope or lattice to a particular in the brain. So if you |
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| 43:01 | on these, this should uh lead to this video. You can see |
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| 43:14 | movement of the neuron along the radial cell here. Yeah. So let's |
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| 43:27 | back into this and you can watch second video on your own too. |
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| 43:34 | , oligodendrocytes are myelination in the This myelination is bi lids. And |
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| 43:42 | talked about one process, the one of the myelin in the PNS, |
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| 43:46 | peripheral nervous system. This myelination is swan cells. So, peripheral nerves |
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| 43:53 | myelinated by Schwann cells. Um And yeah, this is pretty much everything |
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| 44:02 | already talked about except the lid. are responsible for myelination. This myelination |
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| 44:09 | is not easy because what has to is this process by Ligo Denver side |
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| 44:16 | to find the axon and then it to wrap around. So you can |
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| 44:23 | that there's multiple layers of this process wraps around the axon to to to |
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| 44:30 | this installation. And there is at seven if not more myelin basic proteins |
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| 44:38 | are involved in this process of myelin . So there is a number of |
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| 44:43 | that influence this process of myelination. of them, some of these proteins |
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| 44:49 | responsible for initiation of myelination. So cell recognition, initiation of myelination, |
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| 44:55 | proteins of these myelin basic proteins. may be responsible for compaction of how |
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| 45:04 | the wrapping around this and all of have to work in unison in order |
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| 45:09 | form axonal myelination, which is basically of axons and it's very much |
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| 45:17 | So if you have the proper insulation the axon, you can generate an |
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| 45:22 | potential here. This is where they at the SOMA and axon initial |
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| 45:28 | And if it's properly myelinated that action is going to reach the external terminal |
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| 45:34 | it is going to result in the of the neurotransmitter. So proper myelination |
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| 45:40 | the action and also provides for reliable transmission from when the cell generates action |
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| 45:48 | to the synaptic terminal here. And what happens if you start losing some |
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| 45:55 | this insulation. If you lose some these mi sheets around, that means |
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| 46:01 | start impairing the action potential. And that action potential that gets generated here |
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| 46:10 | reaches the synoptic terminal, but maybe much smaller. It started being this |
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| 46:19 | here. And now because of the in myelination, that's much smaller. |
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| 46:23 | now it's actually not enough to be neurotransmitters. So if you don't have |
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| 46:32 | myelination, you compromise the synaptic transmission you compromise the communication between neurons. |
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| 46:42 | we are going to discuss two demyelinating . It's familiar to uh uh some |
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| 46:49 | you and some of you have learned it in other courses. So, |
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| 46:54 | sclerosis is demyelinating disease. What is underneath this picture here, it's a |
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| 47:01 | uh disorder in the CNS. It's called multiple because sclerosis which are lesions |
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| 47:13 | found in multiple areas in the So it's typically not just 10 it's |
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| 47:18 | in the left hemisphere in this area the brain. It's multiple locations. |
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| 47:24 | have uh impairment of oligodendrocytes. The denroy are being attacked and eaten |
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| 47:32 | Multiple sclerosis is an autoimmune disorder. myelin is targeted by immune system and |
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| 47:40 | basic proteins are targeted by the immune . You have CNS inflammation and essentially |
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| 47:49 | disorder causes demyelination and loss of So let's talk about the autoimmune. |
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| 48:03 | why, why is it attacking Who is attacking what it's the immune |
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| 48:12 | ? You have a certain amount of four T cells that are expressed in |
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| 48:18 | cerebrospinal fluid. But if you have , there is a breach of the |
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| 48:26 | brain barrier. So if you have , you have holes that open up |
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| 48:36 | the blood brain barrier, leaky blood barrier becomes leaky if you have |
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| 48:49 | And that's a common theme. If have inflammation and you have a leaky |
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| 48:53 | brain barrier, that means things from blood can easily cross into the |
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| 48:59 | And that number of immune cells T four T cells increases tremendously. And |
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| 49:11 | in a normal state, your microglia releasing cytokines and taking care of normal |
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| 49:18 | of the brain. Once there is and invasion of these immune cells that |
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| 49:26 | start attacking myelin. And once there an infiltration of these cells, uh |
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| 49:37 | start over releasing cytokines. Therefore, is a normal homeostasis. There's a |
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| 49:46 | operating within some normal dynamic range. right. And temperature, what is |
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| 49:54 | dynamic range for your body temperature? don't know, maybe 36 and Celsius |
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| 50:00 | the morning, 38 39 40 when in the sauna back to 30 |
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| 50:07 | that won't happen, will only happen you have fever. If you go |
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| 50:10 | sauna and it's hot outside, you're start sweating. So your body temperature |
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| 50:15 | a homeostasis. It's gonna be about same. If you are in a |
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| 50:22 | and shivering, there might be a in one degree or half a |
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| 50:28 | But you will, your body temperature go from physiological 37 °C to 40 |
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| 50:33 | you have an infection, if you inflammation, especially bacterial infection. |
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| 50:41 | So what is the dynamic range of body temperature? Not much? Just |
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| 50:48 | couple of degrees Celsius fluctuations between 36 say in 38 on, on a |
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| 50:55 | a daily basis, if it goes of this range to 100 it goes |
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| 51:01 | 100 and four and it stays at one can die quite easily actually because |
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| 51:09 | will have a hypothermia induced seizures at and four °C. So this is |
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| 51:16 | this is just an example of what the dynamic range in the system. |
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| 51:21 | will talk about action potentials in the and address that dynamic range as well |
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| 51:28 | between minus 45 let's say and minus . And during action potential, that |
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| 51:35 | range is between minus 45 and positive that's an average. So this is |
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| 51:43 | dynamic ranges and when, when something outside of that dynamic range and that |
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| 51:48 | can be cytokines. So when it's normal dynamic range and normal solitary on |
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| 51:55 | stasis cleanup is going on. You a spike in the cytokines. |
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| 51:59 | it can actually contribute to pathology. There are different causes of multiple |
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| 52:07 | Genetic predisposition doesn't mean that it's genetically cause disease. Multiple genes are involved |
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| 52:15 | multiple chromosomes, infectious factors such as . So, one of the theories |
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| 52:21 | the, is the first brain infection infection on these axons and then the |
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| 52:28 | cells start attacking it and they become and they just keep killing instead of |
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| 52:34 | infection, just keep killing the axon infection was originally environmental factors. Vitamin |
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| 52:41 | is being addressed um in relation to sclerosis, genetic predisposition can be |
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| 52:48 | of course, onset age is typically to 30 years old. Females are |
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| 52:54 | affected uh symptoms is it just really what part of the brain is affected |
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| 53:02 | it could be globally sclerotic or it be, although multiple locations could still |
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| 53:07 | more, let's say to the frontal rather than the occipital lobe. And |
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| 53:13 | could have double vision, muscle painful muscle spasms. So what happens |
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| 53:19 | you lose this myelin, your axons function normally your communication through action |
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| 53:27 | So, neurotransmitter release is abnormal. so now when you're talking about muscle |
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| 53:34 | , that's periphery. Right. It is not the muscle. So |
|
| 53:39 | causes tremors and it also causes very , kind of a clenching of spasms |
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| 53:48 | And that's because I, for I have normal control. So I |
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| 53:52 | tell my my fingers in my I'm fun. Straight out to |
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| 53:57 | Move around. If my myelin has compromised, this is at the level |
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| 54:03 | the CNS. So your peripheral nervous has not been compromised. It's only |
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| 54:09 | oligodendrocytes that affect you. But the that is coming from CNS is called |
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| 54:16 | that's and, and, and the is unreliable. So I have a |
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| 54:24 | and my motor cortex, my conscious cortex, my conscious thinking says motor |
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| 54:30 | , tell this spinal nerve to relax because it's becoming painful. And the |
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| 54:38 | neurons and motor commands and other networks . They're failing, they're failing, |
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| 54:46 | failing. So they may have initiated contraction but they're failing, they're failing |
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| 54:50 | relax the muscles. So the fact on the periphery but it is ac |
|
| 54:57 | disorder that we're talking about. And the same would be, for |
|
| 55:02 | , for Parkinson's disease. When we about the tremors, again, the |
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| 55:06 | is in the CNS. It's not dysfunction and the atrophy of the |
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| 55:11 | And that's why you're having tremors or, or spasms. It's because |
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| 55:16 | the faulty commands, faulty motor faulty muscle relaxation commands and then other |
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| 55:24 | as had a cognitive dysfunction, mental fatigue. Uh There's treatments that are |
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| 55:32 | pharmaceutical treatments, but there's also other that are potentially physical physiotherapy, nutraceutical |
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| 55:41 | diet related therapies activities and so on so forth. And this is a |
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| 55:47 | Institute for Neurological Disorders of stroke, DS. The link to multiple |
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| 55:55 | And uh if you have demyelination of cells in the periphery, it's associated |
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| 56:04 | Charcot mary tooth disorder. And because the improper myelination in the periphery |
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| 56:12 | and it's typically during the development onset adolescent, early adulthood where your muscles |
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| 56:19 | still shaping in your skeletal bones and skeleton is still shaping around the |
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| 56:26 | If you have this demyelination in the , again, you don't. |
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| 56:30 | it's because in the periphery, you have proper control of muscles. |
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| 56:34 | you don't have proper control of You have deformative in your deformities in |
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| 56:42 | arms or in your feet. You weakness quite often. You have curvature |
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| 56:47 | scoliosis of the spine. Uh You have short, shortening of certain um |
|
| 56:57 | , uh tendons, muscle cramping, pain, and the treatment for this |
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| 57:03 | really braces, physical therapy and So the earlier you identify sha N |
|
| 57:09 | , you can place people in the so they can have the muscles more |
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| 57:14 | , therefore, their gate, more and hopefully motor commands more uh symmetrical |
|
| 57:19 | execute executable again. And it's a demyelination, one of the most common |
|
| 57:26 | neurological disorders. So this is this is a genetic disorder, PNS |
|
| 57:34 | due to PNS demyelination. Um And other types of treatment, obviously, |
|
| 57:42 | you have a lot of pain, it, it's painkillers. Yeah. |
|
| 57:54 | , actually it's a, it's it's another kind of a peripheral myelin |
|
| 58:00 | called P MP 22. And there an over expression of that P MP |
|
| 58:08 | . And, uh, what you to keep in mind is when I |
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| 58:12 | over expression and they'll say, if it's over expression, that music |
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| 58:15 | be more myelin. But remember it's interplay of these myelin basic proteins. |
|
| 58:21 | if one is outside the dynamic range the balance, it can throw off |
|
| 58:26 | balance for others too cause improper myelination demyelination. So, um it's similar |
|
| 58:36 | would also be correlated with uh inflammation well in the peripheral nerves that you |
|
| 58:43 | see in the, in the, the CNS. But CNS is autoimmune |
|
| 58:49 | this is uh in inherited genetic OK. We still have quite a |
|
| 58:56 | left and I'm not gonna rush but we're gonna talk about microglia. |
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| 59:01 | gonna talk about astrocytes. We're gonna about morphology of astrocytes. We're gonna |
|
| 59:09 | about blood brain barrier again. And happens with the compromise of blood brain |
|
| 59:15 | ? We will talk about how microglia interact with each other and how these |
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| 59:22 | between microglia and astrocytes are very important a part of normal synapse formation |
|
| 59:30 | But also what happens if you have release of these inflammatory molecules such as |
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| 59:38 | in the tissue, what happens to tissue glial tissue or vascular tissue. |
|
| 59:47 | uh we basically mostly focus on the between microglia and Astros. And some |
|
| 59:55 | these themes about microglia and cytokines and will come back too when we |
|
| 60:00 | for example, Alzheimer's disease. if you look up microglia and Alzheimer's |
|
| 60:05 | , this huge correlation there with with leaky blood brain barrier, with |
|
| 60:10 | of homeostasis or proper homeostasis that all to plaque formations in Alzheimer's disease. |
|
| 60:17 | there's a strong correlation there. And general inflammation uh is sort of a |
|
| 60:24 | a common theme in many neurological And now a lot of times when |
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| 60:29 | have one neurological disorder, you may another condition that we call comorbidity |
|
| 60:37 | And we always wondered, well, causes the coma, if, let's |
|
| 60:42 | you have a genetic mutation that causes disorder like uh MS and now you |
|
| 60:50 | epilepsy. So, is that due the same uh change that happened? |
|
| 60:57 | , is it the same autoimmune destruction causing epilepsy is something different? And |
|
| 61:03 | think that may be inflammation could be linkage that inflammation on its own generated |
|
| 61:11 | one disease can call upon and so to speak a, a comorbidity |
|
| 61:18 | when and how it sequester it, don't know there's probably other factors involved |
|
| 61:23 | well. So, all right. you very much. Enjoy the rest |
|
| 61:27 | this beautiful afternoon and I will see all on |
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