| 00:01 | Okay, welcome back. This is five of neuroscience. Today is Tuesday |
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| 00:11 | 31st the last day. And we essentially today, more than halfway through |
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| 00:19 | material that you will be responsible for midterm exam one. So if you |
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| 00:25 | missed a couple of classes, if missed a couple of lectures, if |
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| 00:29 | not attending in person, uh and just watching these videos, I would |
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| 00:35 | you to probably the best way to the highest. And the exam is |
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| 00:41 | attend the lectures, take notes, the videos, not just watch the |
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| 00:45 | at home. So that's for people are watching this video on video, |
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| 00:50 | video points. And we're going to supposed to talk about neuronal number and |
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| 00:56 | trust, but we're going to finish of the things that we discussed about |
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| 01:01 | then talk about Glia and then see we have time to start discussing resting |
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| 01:06 | potential. But we probably will as cover the lecture material today, there |
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| 01:12 | supplementary and supporting class lecture readings and that I have for you in a |
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| 01:18 | folder and blackboard. So I will using some of these links, as |
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| 01:22 | mentioned. Some of them are to videos that are publicly available. Some |
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| 01:26 | them are Youtube videos and they may commercials in front of them. So |
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| 01:30 | apologize, I'm not responsible for that there. The point is actually the |
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| 01:36 | of the video itself. Okay, we discussed many different things about neurons |
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| 01:43 | if you want to remind yourselves where finished was we spoke about this particular |
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| 01:50 | and we spent, I would say , 10 maybe even 15 minutes on |
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| 01:54 | slide. And there were some he away messages that I was telling you |
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| 02:01 | I was explaining this, I was for you on the board. That's |
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| 02:04 | advantage of being in the classroom. said through the video, it doesn't |
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| 02:08 | clearly show what I write on the , but you can hopefully see very |
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| 02:14 | everything that I write here in So if you look at your lecture |
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| 02:20 | , this is the continuation of 34 the last few slides that we're supposed |
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| 02:28 | discuss and then the 45, it's the same kind of slides, just |
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| 02:34 | reminder and then discussion on glia. what I would like to highlight from |
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| 02:41 | uh slide that we discussed last time particular, we talked about what structure |
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| 02:48 | the brain this circuit is from. we said that this structure in the |
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| 02:55 | is called the hippocampus. We said hippocampus is an Arky cortex or arcade |
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| 03:06 | . Arche cortex because it's predominantly three structure. We talked about how within |
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| 03:19 | excitatory glutamate neurons will have about 80 90% of the total cellular population and |
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| 03:31 | the inhibitory gaba releasing neurons with constitute other 10 to 20% of the total |
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| 03:41 | population. We also talked about how motor GIC neurons are projection neurons. |
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| 03:50 | so if you look at these local circuits that are adjacent to each |
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| 03:56 | the excitatory karam, it'll, cells are glittering, liturgical excitatory are going |
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| 04:02 | communicate this excited for information within the work locally. But it's also going |
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| 04:09 | project this information. So these are neurons and for the most part they're |
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| 04:15 | glutamate releasing and they will interconnect the networks. Now with them these networks |
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| 04:23 | is a variety of inhibitory cells that going to be talking to each other |
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| 04:28 | also going to be influencing and talking the parameter cells excited tourists. These |
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| 04:36 | for the most part inhibitory gaba releasing and their local network into neurons. |
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| 04:43 | they're not projection cells. We said also exceptions to almost every rule. |
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| 04:49 | so this kind of arrangement that you're this arrangement of inhibitory cells and excitatory |
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| 04:56 | , this kind of a ratios that discussing of excitatory overall cells and these |
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| 05:04 | versus the inhibitor overall south. You'll that in the hippocampus you'll see it |
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| 05:08 | the cerebral cortex as well. So lot of times we refer to these |
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| 05:13 | of circuits as canonical circuits because that that there's going to be analogous circuits |
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| 05:19 | you will be able to find if the exact same self sometimes that we're |
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| 05:24 | analogous circuits and connectivity and rules by processing in these neuronal networks happens. |
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| 05:33 | what else did we talk about it's important for semantic memory. So |
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| 05:37 | a structure in the brain that is for semantic memory and also is involved |
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| 05:44 | emotional information processing. So it's the of that memory and also recall of |
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| 05:52 | memory through this hippocampal circuits. And when we looked at the circuit |
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| 05:57 | we said that there is not that variety in the excitatory projection cells. |
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| 06:03 | these are the parameter cells and their cells and that we cannot really distinguish |
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| 06:09 | one from another morphological e we can that some of the cells are located |
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| 06:14 | the stratum ready atom layer versus stratum middle versus stratum orients. But more |
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| 06:20 | . These green and turquoise parameter they look analogous to each other and |
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| 06:28 | cannot really distinguish them based on whether projections, their projection cells, they |
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| 06:33 | glutamate. But these different some types cells we said well express slightly different |
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| 06:39 | of genes. Therefore they will carry slightly different substance of molecules, proteins |
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| 06:45 | chemicals inside of them. So some the parameter cells will be called in |
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| 06:49 | positive and others will be called in negative. And for the most |
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| 06:54 | this is the only distinguishing distinguishing feature these parameter cells, not even their |
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| 07:00 | firing rates and firing properties that we'll in a second. Now when we |
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| 07:07 | at the circuit and we said that other cells that are labeled one through |
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| 07:10 | . These are actually the inhibitory local into neurons and they can be distinguished |
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| 07:18 | on morphology. So where they're located , Selma's, in which layer based |
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| 07:23 | the dendritic morphology, whether they have projecting them rights or vertically projecting |
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| 07:30 | And finally based on the locations of inhibitory synapses, these yellow cups that |
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| 07:37 | will be forming in controlling the activity these excitatory cells, projection cells. |
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| 07:44 | finally we still need to use markers as uh evolvement markers or other self |
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| 07:51 | markers in order to distinguish and the . Some of these inhibitory interneuron that |
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| 07:57 | actually look very similarly morphological and may have the same functional output. When |
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| 08:05 | talk about functional output. That's when start talking about the last really very |
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| 08:11 | feature that will allow us to subtype different subtypes of neurons into that. |
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| 08:17 | was 21 in the previous slide, example, for the inhibitory cells. |
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| 08:22 | this is an example of a wholesale it. The patch clamp, wholesale |
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| 08:27 | These are the micro electors the scales you're looking at the diameter of the |
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| 08:32 | . The neural is about 10 micrometers the diameter of this electrode tip is |
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| 08:37 | than one micro meter across. Democrats about one micrometer. Some of the |
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| 08:42 | axons shooting off here, our half micrometer or less in diameter. So |
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| 08:49 | approach these cells using the infrared Remember that in this type of microscopy |
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| 08:55 | don't need to stay neurons in order visualize neurons, we record electric physiological |
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| 09:01 | from these cells and both of these through these electrodes will receive identical inputs |
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| 09:08 | that input is an electrical stimulation in form of deep polarization of the |
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| 09:13 | But the cell on the left produces very fast frequency response and their action |
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| 09:21 | . These are individual action potentials and cell on the right while it receives |
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| 09:25 | same stimulus, it fires it much lower frequency than the cell on |
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| 09:32 | left. So during the experiment there also dies that can be placed inside |
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| 09:38 | electorate. They're called neuro biotin or and dice. And these dyes will |
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| 09:45 | leak into the neurons that you're targeting the recordings. And after the experiment |
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| 09:51 | can use the modern day in camera up camera lucida microscope. If you |
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| 09:57 | was used by ramon alcohol to reconstruct in modern day, you can use |
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| 10:03 | neuro lucida software with a little bit human health and reconstruct the precise morphology |
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| 10:10 | these neurons. And so that you demonstrate their precise morphology location and finally |
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| 10:18 | stated cross reacted with specific cellular So all of these are essentially necessary |
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| 10:26 | order to convince the reviewers in high high level publication magazines for neuroscience that |
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| 10:35 | recorded from Cell subtype number seven, subtype number two, cell subtype number |
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| 10:44 | and so on. So there's some that we're we're trying to standardize and |
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| 10:50 | order to definitively prove a subtype of cell. You have to involve all |
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| 10:56 | these techniques and the sustaining techniques would done with you know histology immunities to |
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| 11:03 | . Uh And these dyes the diet goes in is called neuro Buyten also |
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| 11:09 | called biocyte in. And this is example of now neo cortical circuits. |
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| 11:17 | neocortex is a new cortex X. structure and this is a patch of |
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| 11:21 | neocortex and this patch of neocortex. is an example with each one of |
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| 11:27 | arrows points to recording that was done all of these different neurons in this |
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| 11:33 | circuit here in the neocortex and all these neurons that receive the same |
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| 11:39 | But they produced a very different outfit their outfit is different. Some of |
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| 11:46 | produced these bursts of action potential others have continuous fast firing, others |
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| 11:56 | slow and firing, Others are delayed stuttering. So so these are what |
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| 12:08 | call cellular dialects. They all speak same language. They all produce action |
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| 12:14 | but the dialects are different and all these 100 50 or so different subtypes |
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| 12:21 | cells will have slightly different dialects and will produce action potentials in different patterns |
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| 12:29 | this is important for the processing the of collectivity. The complexity and processing |
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| 12:36 | the complexity and cellular composition of these networks stems from the variety and the |
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| 12:44 | of the inhibitory cells local network into and so parameter cells for the most |
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| 12:51 | will produce the same accommodating it's called accommodating patterns. So this is the |
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| 12:58 | of the excited through projection cells and them to be positive or negative. |
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| 13:03 | will still speak the same dialect. the inhibiting internet are going to be |
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| 13:09 | for all of these different subtypes of . And this is just in this |
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| 13:15 | in here in the neocortex. So is some of the takeaway information and |
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| 13:23 | fact that you have diversity of these neurons and because of their diversity and |
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| 13:31 | of the molecules that they express and channels that they express and the way |
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| 13:35 | conduct ions across plasma membranes, influences the types of frequencies and responses that |
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| 13:41 | can produce to the same stimuli. , so this kind of a recording |
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| 13:47 | be done, as I mentioned to using a microscope with infrared microscopy and |
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| 13:54 | can if you're really good and potentially simultaneously in vitro in a dish from |
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| 14:00 | cells. Six cells. It was maybe that done eight recordings from eight |
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| 14:06 | at the same time. But beyond , that's kind of where the stretch |
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| 14:11 | the experimental capability stops and the automated of these types are not yet at |
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| 14:17 | level where they can be done using robotics but in any case uh sometimes |
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| 14:24 | use really sophisticated equipment. This was setup when I was doing my second |
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| 14:31 | at George Mason University in Fairfax Virginia I started studying epilepsy. And the |
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| 14:38 | why I was uh uh stubborn enough spend hours and trying to record from |
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| 14:45 | or three neurons simultaneously because they wanted know whether the inhibitory or excitatory cells |
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| 14:53 | the hippocampus in that area, which were basically responsible for starting seizure activity |
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| 15:01 | . That was the question that I addressing for a number of years using |
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| 15:05 | techniques and sometimes you work late in lab and you run out of the |
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| 15:10 | holders and if you notice this is pen and it is on a sophisticated |
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| 15:19 | , but I didn't have anything This would be like a more proper |
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| 15:23 | to hold it. We didn't have else. So sometimes you just innovate |
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| 15:27 | you go if you have to get good result. Okay, so at |
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| 15:32 | point, uh we're continuing with with and as I mentioned, your other |
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| 15:41 | , which is more five lecture slides essentially the same uh as the continuation |
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| 15:47 | 34. So glia glue for a time, we're kind of a understudied |
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| 15:57 | subtypes of cells, they're not right? The Glion and Glia, |
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| 16:05 | not excited or they're not inhibitory. Glia, in fact, like I |
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| 16:12 | from the very first slide I said like chocolate chips in the cookie. |
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| 16:18 | dough is ugly and chocolate chips and . So there's a lot more dough |
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| 16:23 | chocolate chips. And the same with cellular uh ratios. There's a lot |
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| 16:28 | glial cells versus neurons. So glial for a long time were thought to |
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| 16:35 | serving a passive property sort of to and insulate neurons. And they were |
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| 16:43 | considered very interesting until the last two . Many discoveries in neuroscience have led |
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| 16:49 | to understand that we are intricately involved this. Try synaptic, what we |
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| 16:56 | communication. So glia is involved in the communication between neurons. Glia is |
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| 17:03 | in migration of neurons to find their and their destinations are involved in synaptic |
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| 17:10 | and synaptic plasticity. And so they're even have their own distinct ways in |
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| 17:16 | they communicate to neurons as well. addition to all of this. So |
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| 17:22 | are different subtypes of glial cells at end of this uh presentation. You'll |
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| 17:32 | this slide that summarizes and you actually the slide already when we talked about |
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| 17:38 | 19 infections. So you can see micro glial cells the astra sides a |
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| 17:45 | demo besides and they go down the are responsible for my elimination in the |
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| 17:50 | . N. S. Astrocytes are much involved in the synoptic control and |
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| 17:57 | transmission between neurons and influencing the synaptic especially between the excitatory cells and in |
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| 18:04 | excitatory cells. Michael glial cells are smallest and the most mobile elements in |
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| 18:12 | brain. They're the scavenger cells they activated when there's a need for repair |
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| 18:19 | a damaged are also involved in control inflammation and release of side of kinds |
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| 18:26 | the normal, regular, controlled release side of kinds of normal function. |
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| 18:31 | essentially it is the response to microbial , the immuno inflammatory response that calls |
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| 18:41 | the brain to start fixing itself, itself. So michael glial cells are |
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| 18:50 | for this function. And uh let's at the video here. What you |
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| 19:01 | see in this video is this dot appears here now. What this dot |
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| 19:07 | is is the site of injury right . So this is where the injury |
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| 19:14 | is where this dot is. And else sustained in this particular video? |
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| 19:20 | micro glial cells. So all of not all neurons, but these are |
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| 19:25 | the neurons that are glowing glia that glowing are micro glial cells. |
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| 19:31 | this is leo specific marker for micro south. So there's a side of |
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| 19:37 | . You'll also see that there is time lapse here um which probably gets |
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| 19:46 | maybe covered by this top menu. then you have the 10 micro meter |
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| 19:54 | space reference here. Okay, So you're seeing is this is about 40 |
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| 20:08 | into it. And so when the happens at first in this area, |
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| 20:17 | first thing that happens is you can that micro glia start reaching out and |
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| 20:25 | their processes and migrating their processes towards side of the injury kind of surrounding |
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| 20:30 | site of the injury. And that's within minutes and you'll actually, sometime |
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| 20:39 | . You can also see time lapses the cells that were located here. |
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| 20:45 | most of the microbial cells are located closer now to the site of the |
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| 20:51 | . So if you if you jump can see that this distance is |
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| 20:58 | So micro glial cells that the most elements in the brain of the smallest |
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| 21:06 | and they're responsible for amassing this response injury. And uh potentially not only |
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| 21:16 | but also infection because they will be following infection. And when you talk |
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| 21:22 | COVID-19 actually a lot of times will hear cytokine storms and control cytokine storms |
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| 21:29 | these uh there's a normal response of brain and the body's to produce inflammation |
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| 21:35 | release cytokines so that the cell immune can be activated. But when the |
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| 21:44 | of khan and this inflammatory molecules, inflammatory molecule are released uncontrollably, then |
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| 21:53 | can have uh too much of And that is also. Yes. |
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| 22:12 | so maybe the question is, can rebuild neurons? Probably not? You |
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| 22:17 | , there is no regeneration of So once neurons are injured, they |
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| 22:24 | regenerate. We have some stem cells the brain. So new neurons can |
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| 22:30 | born to very small extent, especially adult brains and to a larger extent |
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| 22:35 | younger brains. Um So they're responsible of for cleaning up around the side |
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| 22:42 | the injury and for making sure that is a sufficient repair an immune response |
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| 22:52 | gets generated around the side of the physically. You cannot rebuild neurons. |
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| 22:59 | is no environment in the C. . S. By which these neurons |
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| 23:04 | rebuild their processes uh Once they have severed. Once they have been |
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| 23:11 | That's not the case in the Because you can know from probably experiences |
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| 23:18 | reading that if you have a damage the nerve and the arms sometimes it |
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| 23:23 | it can repair itself, it can some time but it can be a |
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| 23:27 | and repair the generation because the peripheral system, the environment is different, |
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| 23:32 | chemical environment is different. And of again you talk about within the context |
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| 23:38 | plasticity, any damage to the If you are in the early stages |
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| 23:43 | this development, you're more likely to whatever damage has been caused as as |
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| 23:52 | to if this happened to more mature person. Okay so we are going |
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| 24:02 | into the never transmitter and ion uptake astrocytes and we'll talk about that. |
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| 24:08 | astrocytes are not just responsible for We'll talk about the fact that astrocytes |
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| 24:15 | responsible for absorbing glutamate, the major or neurotransmitter and actually breaking down glutamate |
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| 24:25 | getting some of that glutamate back to excited projection cell. Astrocytes are also |
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| 24:34 | and comprise a portion of the, glad it's yours, a portion of |
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| 24:40 | blood brain barrier. Uh And so is and feet of the astra synthetic |
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| 24:49 | that hug the little capillaries the blood . And they patrol essentially what gets |
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| 24:56 | the brain. Remember that there is barrier. And we'll discuss that in |
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| 25:00 | second now. Number four guide neuronal and process outgrowth, neuronal Agrio |
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| 25:09 | So when neurons are born in the brains, they're born in a few |
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| 25:16 | areas in the brain, they're not . So neurons that are in the |
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| 25:21 | cortex here in area 17, broadband 17. They're not born in the |
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| 25:27 | cortex, neurons that are in the cortex and not born in the temporal |
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| 25:33 | . They're born in specific zones in brain, more on the inside, |
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| 25:38 | of the brain. And then neurons migration. They migrate and they migrate |
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| 25:47 | radio glial cells. The radio glial becomes like a lattice the neurons to |
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| 25:53 | to their final destinations. So neurons to find temporal lobe and they have |
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| 26:00 | find auditory cortex. It's a six structure when they're destined maybe to be |
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| 26:07 | layer four. And that is gonna their final mail mailbox is layer four |
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| 26:14 | a specific column in auditory cortex and temporal lobe. So there's a significant |
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| 26:20 | of migration that happens. And this an example of this kind of cellular |
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| 26:29 | that you would see. And was during these uh early cellular migrations and |
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| 26:40 | is a neuron and it's using radio cell like a rope and it's kind |
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| 26:47 | just climbing along the road, its destination. But the membrane actually becomes |
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| 27:00 | . So the cytoplasm becomes continuous. it's using the sliders with radial glial |
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| 27:07 | . But it's very important then this of providing the proper lattice and guiding |
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| 27:16 | into specific areas and specific tortoises and and the networks um with a much |
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| 27:25 | like back bouncing back and forth. like I wish I wish I |
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| 27:34 | Maybe it's a little little guiding maybe it's even some piece of dirt |
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| 27:42 | something. Something in the solution. . I don't think that was in |
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| 27:48 | figure legends out good observation because you know. Maybe there's like a little |
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| 27:55 | and it's leading the south to migrate certain distances. So astrocytes again come |
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| 28:03 | here as blood brain barrier. Already , they're also involved in growth factor |
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| 28:10 | . So like slow growth factors that influence the actual growth of individual. |
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| 28:17 | . How long does it take to ? It's a good question. Uh |
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| 28:27 | this case this migration is short distance this movies. It's I think it's |
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| 28:34 | minutes to migrate some micro meters and that could be uh pretty comfortable what |
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| 28:42 | happening in the brain. So probably to two weeks for neurons to migrate |
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| 28:47 | establish themselves and that is happening mostly the very early development of Lebron. |
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| 28:56 | So is the migration from the same all neurons or very uh well it |
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| 29:09 | be the same time because they have come from these zones where they're sort |
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| 29:16 | like stem cells and at this stage still very potent and they then may |
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| 29:24 | uh an inhibitory cell versus an excitatory or inhibitory cell number seven in hippocampus |
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| 29:31 | to previous charge. So it is . This process is happening though within |
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| 29:39 | demands of giving birth to new And these neurons of migrating is the |
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| 29:45 | structures to differentiating during early development. then when you're born you have the |
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| 29:54 | and the structures of the brain. the connectivity now is what's really changing |
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| 30:00 | lot post natively. So. All . Uh So the the the glia |
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| 30:11 | we're talking about, they are very . They're very important. The control |
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| 30:19 | genesis, the formation of new synopsis and genesis they control synapse numbers |
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| 30:27 | they influence the dendritic spine numbers And the contact numbers synaptic function and |
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| 30:36 | plasticity. But unlike neurons that we talked about and we said that neurons |
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| 30:44 | this dialect and the language of action and that's how they communicate this information |
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| 30:50 | another. Because this language of electrical potentials translates in the chemical neurotransmitter release |
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| 30:58 | certain patterns. Paglia is not capable producing action potentials. They don't produce |
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| 31:05 | potentials. But instead they have large of calcium and they passed this calcium |
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| 31:13 | between glial networks that are interconnected and they communicate with what we call via |
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| 31:21 | calcium waves that are much slower. an action potential is 1 to 2 |
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| 31:27 | in duration, agreeable calcium wave can a second longer. So there are |
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| 31:34 | temporal processing scales, neurons are very but also neurons can be slow. |
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| 31:43 | there's a whole range of dynamic range the speed and the frequency with which |
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| 31:51 | process. The slowest neurons can process just within one or two hertz |
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| 32:00 | One or two spikes a second. the fastest neurons can produce 600 spice |
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| 32:06 | 2nd. 600 hertz. Very very . And the action potential so very |
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| 32:14 | fast. 1 to 2 milliseconds in . And leo calcium waves are very |
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| 32:22 | slow. And they don't speak that . Real cells. They don't speak |
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| 32:30 | language of the actual potential. So don't have that same dialect. Their |
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| 32:35 | is calcium waves. Yeah. So we talk about insulation it's very important |
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| 32:55 | neurons and that is my elimination and you have in the periphery periphery. |
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| 33:01 | nerves are Myelin ated with Schwann So all of the uh nerves that |
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| 33:09 | in the periphery. Okay and are out of the brainstem and into your |
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| 33:16 | . Their peripheral. They're not in C. N. S. So |
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| 33:21 | Myelin ated with Schwann cells and the nervous system, neurons are pollinated with |
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| 33:31 | genital sites. The big difference is once one cell is just one single |
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| 33:40 | of Myelin. And for illegal Deandra they can have multiple processes and one |
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| 33:48 | cell can form multiple segments on multiple that belong to different neurons. So |
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| 33:56 | cell is just one segment, one . And for legal de emphasizes multiple |
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| 34:03 | in the cns. So there are that can happen with regard to Myelin |
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| 34:12 | and my elimination process is controlled where have the precise compaction of Myelin. |
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| 34:22 | when myelin wraps around ourselves, wrapping around multiple times and forming the |
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| 34:30 | is you also having a certain compaction these processes are running, wrapping around |
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| 34:39 | there's d my elimination. Now deem can occur. For example, if |
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| 34:45 | have an infection if you have an myelitis which will cause inflammation and can |
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| 34:55 | d my elimination or loss of Myelin you can reproduce that by basically having |
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| 35:03 | injections of uh in the animal brains infections that can happen in animal |
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| 35:13 | There are seven related proteins. So not just one protein that is responsible |
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| 35:19 | the proper compaction. Their myelin associated as an example that is responsible for |
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| 35:29 | of Myelin Nation. And to initiate elimination. It's very important that delicate |
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| 35:36 | recognizes neuron and neuron says, hey we can play together, you can |
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| 35:43 | around me so the cells cell Now we'll come back and talk about |
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| 35:51 | Marie tooth disease. Uh This just out that it's not necessarily that D |
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| 35:57 | Nation is a result of a decrease a certain protein or not enough of |
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| 36:02 | certain protein because it's interaction of seven proteins. And then periphery D. |
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| 36:07 | Nation can be a result is too of one type of protein which is |
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| 36:14 | myelin protein PMP 22. And we'll Charcot Marie tooth disease in the following |
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| 36:23 | , yep, we are talking about associated with and systematic and no |
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| 36:41 | Yeah. Yeah. I mean they they will they may have a different |
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| 36:47 | of these seven or more so of myelin compaction and Myelin basic proteins that |
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| 36:54 | controlling the installation process, wrapping It's not like something with the and |
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| 37:03 | for the what uh we're not necessarily at the exact subset of proteins that |
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| 37:14 | used for each expression. That's that's what we can cover in this |
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| 37:19 | But there will be variations. And course it will be different self self |
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| 37:25 | that has to happen for a in case a motor neuron or a cranial |
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| 37:35 | to be recognized by Swanson. Rather than a inhibitory gaba neuron be |
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| 37:44 | by uh legal lymphocyte. So, there are slight variations in this protein |
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| 37:53 | expressions and how they interact with each . Um We won't get into details |
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| 38:00 | that. But the most important thing take away from this slide is that |
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| 38:08 | sclerosis which is not going up Well here in yellow, multiple sclerosis |
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| 38:15 | a disease is a neurological disorder. one of the common neurological disorders. |
|
| 38:22 | when we talk about neurological disorders what are the things that come to |
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| 38:27 | when you think about multiple sclerosis? you thinking about developmental mental retardation? |
|
| 38:34 | an autism spectrum disorders or fragile acts ? Are you thinking that multiple sclerosis |
|
| 38:41 | um, aging disease will be observed the onset of it will be uh |
|
| 38:48 | population. And it turns out that sclerosis, the onset of the disease |
|
| 38:55 | happens in the 30s. So this a disease. Now when we're talking |
|
| 39:00 | that also has a genetic component. you will have mutations, for |
|
| 39:07 | chromosome 18 mutations have to have to . He also has to be recessive |
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| 39:14 | order for you to express the disease have the phenotype, which the symptomology |
|
| 39:23 | the phenotype is tremors and convulsions. so you will hear a lot of |
|
| 39:31 | people with multiple sclerosis, what is with multiple sclerosis is that you have |
|
| 39:38 | significant demand elimination of loss of So multiple sclerosis is an auto immune |
|
| 39:50 | . That means that in this case body itself or in this case the |
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| 39:58 | itself starts killing illegal. Down beside getting rid of the myelin and |
|
| 40:07 | Now, something is wrong with the of illegal genocides and instead myelin and |
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| 40:15 | down the sides of being recognized as foreign invader which needs to be |
|
| 40:22 | So this is essentially a response that you're having now. Uh if you |
|
| 40:33 | about symptomology, humans uh multiple sclerosis lot of times you will hear that |
|
| 40:42 | can't control the movement of their So there's a tremor component. Uh |
|
| 40:49 | is a component of spasms, muscle and locked up muscles because of the |
|
| 40:58 | now being the myelin ated, it carry the infosys properly. Those patterns |
|
| 41:03 | action potentials are not being carried And in this case this de milo |
|
| 41:09 | is happening in the C. S. So the commands that are |
|
| 41:13 | taking place from the motor cortex are commands. And you can essentially, |
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| 41:21 | you think about it first, if demolish nation in the areas of control |
|
| 41:27 | things like movement of hands and things the progression of the disease and subsequent |
|
| 41:35 | Allan nation further the marination of neurons globally can lead to all sorts of |
|
| 41:41 | , cognitive problems and mental problems and sorts of things like that. So |
|
| 41:48 | we have Have a model here and is a cross section through lenny axons |
|
| 41:54 | really nice and thick ma domination around axons. And this is a genetic |
|
| 42:01 | that we refer to a shiver model this case. You have a mutation |
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| 42:07 | chromosome 18. You have the model nation And these animals in this case |
|
| 42:13 | rodents, they will be shivering. they will be reproducing and manifesting some |
|
| 42:19 | the symptomology of traumas and spasms and convulsions. Uh Following the Myelin |
|
| 42:29 | And this example shows that you have trance faction. Gene transfer action here |
|
| 42:36 | normal genius transfer active in this case this completely very scant Myelin you rebuild |
|
| 42:45 | of this installation in my elimination around excellence here with this, with this |
|
| 42:50 | therapy. A subject. Yes. , something like that. Be humans |
|
| 42:55 | do that like that. I What is that like a nation in |
|
| 43:01 | ? There are some things I've heard what from from a perspective like what |
|
| 43:07 | cause different stuff like like that right to my elimination of humans. You |
|
| 43:15 | , I wish we knew. But if you have the myelin nation as |
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| 43:23 | sclerosis and these are the causes of sclerosis. Uh there probably is some |
|
| 43:29 | induced imagination. It can happen. obviously you can have infection induced the |
|
| 43:36 | nation. So some of the severe infections and encephalitis. You know, |
|
| 43:43 | talked about how when COVID-19 gets into brain will have neuro degeneration. So |
|
| 43:49 | have everything that you have demolished Slowly, neurons unraveling and being able |
|
| 43:54 | fire properly and going into program cell apoptosis or necrosis. So that there |
|
| 44:03 | instances, but it's not that it known that oh well if you consume |
|
| 44:10 | much caffeine or if you consume too nicotine or ethanol alcohol then you know |
|
| 44:18 | that is meant to cause the violent . Mhm. So, but I |
|
| 44:24 | need to refresh and look at if anything known with some of the substances |
|
| 44:28 | common substances that that that we Well, you know, patients are |
|
| 44:50 | Parkinson's patients because in that case dopamine are inhibited severely or harmed severely, |
|
| 44:57 | that progression I know it has a onset and I know that it's treatment |
|
| 45:03 | also different in terms of uh the for text right here in the |
|
| 45:07 | So I was wondering like because it at a later age and progresses indicates |
|
| 45:13 | M. S. Where it's almost . Which a that's a that's very |
|
| 45:26 | to say. So the question is Parkinson's disease and you're correct to say |
|
| 45:31 | Parkinson's disease is a motor disorder, is a lot of significant amount of |
|
| 45:38 | and Parkinson's disease. Uh Now it with dopamine signaling, so it's |
|
| 45:48 | No, no. And it's later . So it's typically fifties and older |
|
| 45:57 | Parkinson's occurrences and diagnosis. No, , it is loss of dopamine logic |
|
| 46:10 | and dopamine cells and dopamine receptors for . So it is so it is |
|
| 46:16 | . I'm glad you're thinking about it comparing especially the motor component, but |
|
| 46:21 | will see that some M. Patients will also have seizures convulsions. |
|
| 46:29 | patients may also have seizures fragile X will also have seizures. So this |
|
| 46:36 | a pretty comical morbidity if you have app set and balance or upset Violin |
|
| 46:42 | or connectivity in the cells. Um , maybe what you're getting at is |
|
| 46:48 | can somebody diagnose one person with a versus Parkinson's disease? If they if |
|
| 46:56 | if they're doing it purely based on , the tremors that may not be |
|
| 47:02 | . So then you would go through modern political day testing potentially for markers |
|
| 47:08 | things like that and genetic tests that indicate something or you would do another |
|
| 47:17 | slew of behavioral tests on that So yeah. And sometimes, you |
|
| 47:26 | , you know what diagnosis you have also know in clinical world diagnosis sometimes |
|
| 47:33 | not definitive. And sometimes clinicians will that you have one condition. And |
|
| 47:41 | years later let's say it's actually you know, in oncology a lot |
|
| 47:47 | times when let's say somebody has a and they study that growth and |
|
| 47:59 | Uh apparently 20 the pathology and the is wrong. So, so this |
|
| 48:09 | an example where, you know, hospital thinks that you may have one |
|
| 48:14 | of cancer. Another hospital thinks you another type of cancer or they think |
|
| 48:19 | you don't have cancer. So that's and it's all modern tools and really |
|
| 48:26 | doctors looking at it and they still a different interpretation and based, you |
|
| 48:31 | on in this case, even on pathology, not even in the symptomology |
|
| 48:35 | markers and some, you know, to visualize brain structures. Yeah so |
|
| 48:52 | second disease that we will discuss with and you do have too much of |
|
| 49:00 | P. M. P. Two this case 17 G. Duplication. |
|
| 49:07 | this is a normal stain. And you can clearly see duplicated stain stain |
|
| 49:14 | the gene and the podium as This is the sharp cutlery tooth. |
|
| 49:19 | can see normal violin layers and then can see a loss of violence. |
|
| 49:24 | this is a developmental condition and this in the periphery. Okay so we're |
|
| 49:33 | . N. S. For multiple . We're not talking about peripheral Myelin |
|
| 49:38 | . Why two different cells sometimes right house and this is in the |
|
| 49:47 | typically in the lower limbs. When have a demand the nation and shark |
|
| 49:52 | american. And if there is no for the disease that's Entomology is that |
|
| 50:00 | will see impaired gait. You will a person that is walking and quite |
|
| 50:07 | they will be wobbling sideways more than . So the forward motion is more |
|
| 50:15 | because the legs typically get slanted outwards there is uh difficulty in maintaining the |
|
| 50:27 | and the gate as the person So there's extra effort in that what |
|
| 50:35 | is because there is no installation on nerves. The impulses don't get sent |
|
| 50:42 | to the muscles. And if there uh the Agnes is that is not |
|
| 50:48 | enough Charcot merited disease then you can up with a lot of bodily |
|
| 50:55 | especially in lower limbs. Very But if it is detected very |
|
| 51:02 | there's a possibility of placing a person embraces to help keep the symmetry. |
|
| 51:10 | that would help the person walk basically symmetrical forward motion kind of way. |
|
| 51:20 | now this is something that is So this is due to do my |
|
| 51:28 | and typically curse and was diagnosed in , early life. Yes, |
|
| 51:47 | once the, once the during the , your muscles are uh moving your |
|
| 51:57 | and your bones are growing. And you form into a mature adult, |
|
| 52:03 | it's really you cannot really shape anymore it grows. But there's probably some |
|
| 52:11 | that is used from maybe soft braces things like that and sometimes crutches |
|
| 52:20 | Okay, so two disorders that are to myelin multiple sclerosis, Little shark |
|
| 52:28 | , married tooth. And so these all of the cells that we're talking |
|
| 52:34 | , The good emphasized ostracized micro You have these dependable cells that are |
|
| 52:40 | the cerebral spinal fluid space from what call the interstitial spaces between the cells |
|
| 52:45 | the dependable cells are thought to be potent, which means that they can |
|
| 52:51 | developed into other types of glial This is the blood brain barrier that |
|
| 53:00 | discussed from almost the first name this . What's in the blood is not |
|
| 53:06 | the brain and that is because you the barrier this barriers form. First |
|
| 53:15 | all, you have the yourselves, is the blood vessel walls inside you |
|
| 53:22 | the blood of surrounding parasite cells. then you have the astro glial processes |
|
| 53:32 | between then to feel yourselves, you the tight junctions. So when things |
|
| 53:38 | cross through the blood brain barrier are small molecules, molecules that are fat |
|
| 53:47 | because they have to cross through the of the south molecules that have transporters |
|
| 53:55 | have facilitators that have receptors that combined be transported. So the blood brain |
|
| 54:03 | is very important because if you consumed lot of uh certain level of ions |
|
| 54:12 | potassium that goes from your gut into blood, it doesn't mean that all |
|
| 54:19 | it or all of the substances that into the blood of men across into |
|
| 54:24 | brain. But if you are thinking neurological drugs and designing neural pharmacological substances |
|
| 54:36 | treat diseases, what is the most way that people take their medications orally |
|
| 54:46 | the tablet? Now, gummy or capsule pill. What happens with |
|
| 54:58 | You put it in your brain, ? You open the box, put |
|
| 55:01 | your brain and close it. So goes into your it goes into your |
|
| 55:09 | acidic environment. It goes into your Dropth into your stomach ph 3.3 oh |
|
| 55:22 | and gets starts being digested, goes your digestive system into the God, |
|
| 55:32 | ? Some of it going through the . Uh and then how does it |
|
| 55:39 | into your brain it gets absorbed right the micro villain or God and goes |
|
| 55:48 | the blood and then from the blood goes into the brain. So a |
|
| 55:54 | painkiller, acetaminophen or ibuprofen Advil. it instant? Is it 10 seconds |
|
| 56:06 | you have a mild pain or a headache? What is the doctor |
|
| 56:11 | You have to wait for 1520 minutes sometimes it's half an hour before or |
|
| 56:18 | even longer. And some people depending how they process it through their digestive |
|
| 56:25 | . So if you're treating a neurological now you want to have a drug |
|
| 56:32 | after it gets into the blood can pass through the blood brain barrier. |
|
| 56:38 | guess what? Only a fraction of you swallowed in your mouth gets into |
|
| 56:43 | blood and only a fraction what's in blood gets into the brain. And |
|
| 56:51 | is why when you watch commercials on for example in medication for seizures, |
|
| 56:58 | or depression. Something to do with brain function and then you will hear |
|
| 57:07 | if you are taking this medication you have all of these potential side |
|
| 57:13 | So and the side effects will be and nausea and diarrhea or constipation and |
|
| 57:22 | in the gut. Why why is ? Because you're trying to treat the |
|
| 57:28 | condition But a lot of the receptors lot of the targets in the brain |
|
| 57:32 | also shared in the system systematically in body. Also, if you're trying |
|
| 57:37 | get something into the brain, you're have to have a higher concentration if |
|
| 57:43 | digesting the digestive system. So uh 19 can get in through the nasal |
|
| 57:54 | . So can the drugs actually. there are some nasal sprays and nasal |
|
| 58:00 | can be quite effective in actually delivering substances more directly into the brain, |
|
| 58:07 | it doesn't have to bypass the blood barrier. Because we talked about the |
|
| 58:11 | anatomy that you have in the in formation the crib reform played in the |
|
| 58:17 | reform formation where the olfactory nerve endings out here. So it's a |
|
| 58:24 | It's a challenge if you want to a very effective drug that you have |
|
| 58:29 | swallow, it's a challenge to deliver to the brain. It's easy to |
|
| 58:35 | drugs to the stomach. Uh but difficult to get it through the blood |
|
| 58:41 | barrier. And what happens when we about covid 19 is when there is |
|
| 58:47 | and there's inflammation or if there is , the blood brain barrier becomes loose |
|
| 58:57 | this tie junctions during infection are not as well what is in the blood |
|
| 59:04 | what is in the brain. So is an added level of complexity and |
|
| 59:09 | that can stem from the loose blood barrier, so to speak. |
|
| 59:15 | thinking forward. Uh we're thinking about drugs, we discussed oral nasal, |
|
| 59:27 | good way to get things bypassing digestive is inhalation into the lungs absorption to |
|
| 59:34 | blood that goes into the brain and of the inhalers or inhaling medications are |
|
| 59:42 | to target the lung function. Not else. But I and that's because |
|
| 59:51 | creatures of comfort and habit. You , pop an Advil versus imagine you |
|
| 59:57 | to put it up in the nose you know, do that. Another |
|
| 60:01 | way to deliver things is suppository which vaginal or anal suppository. Why? |
|
| 60:12 | it doesn't get digested in the gastric , it bypasses the liver metabolism. |
|
| 60:18 | there are different advantages of how you and deliver things into the blood. |
|
| 60:22 | that's something for you to start thinking . Uh There's a lot of you |
|
| 60:28 | we'll end up doing something with pharmacology neuro pharmacology or the science of. |
|
| 60:35 | . So would you say that if is having a seizure and I know |
|
| 60:40 | used to help treat. What's You say that you perform for somebody |
|
| 60:49 | having procedure may be more effective So for CBD or cannabidiol, the |
|
| 61:05 | approved pharmaceutical preparation is a tincture. a 10% CBD tincture called the |
|
| 61:15 | This is the CBD that's by prescription there is C. B. |
|
| 61:22 | That is subscription online or in the when you talk about pharmacological drugs. |
|
| 61:33 | only 10% CBD that's approved for the of seizures, epilepsy and it's uh |
|
| 61:42 | a pharmacological substance. Now what you're about the other CBD that is |
|
| 61:49 | These are federally non regulated substances that state regulated to some extent. And |
|
| 61:58 | actually just came up with a statement that uh CBD is too dangerous to |
|
| 62:05 | in supplements on the federal level. , but the state of texas for |
|
| 62:12 | , allows the sales of CBD as guess is something a supplements, you |
|
| 62:18 | ? So um It works efficiently as tincture for these Children that have seizures |
|
| 62:26 | epilepsy, but its high concentration of , it's 10% ethanol days, has |
|
| 62:31 | other oil carriers and sesame seed oil the formulation. So it's a it's |
|
| 62:36 | it's a pretty, pretty standard pharmacological from like after all, and sesame |
|
| 62:43 | oil perspective, but it's very high and just so you know that to |
|
| 62:49 | kids to help them with seizures in , They use 10 mg per kilogram |
|
| 62:57 | this. So adult is about 60 10 mg times 6600 mg per |
|
| 63:07 | Or sometimes multiple doses a day. with people use recreationally or for lower |
|
| 63:16 | uh preparations with CBD. Uh this Within a range of maybe 5-20-40 mg |
|
| 63:27 | CBD period. So it's, we know a lot about like the dozing |
|
| 63:33 | what it can do, how it different people differently too. Just like |
|
| 63:37 | any other drug uh mm, that's good question. So both. There |
|
| 63:51 | examples where it can stop seizures, typically it is used as a as |
|
| 63:59 | a regular um kind of a regiment intake. Not necessarily added on to |
|
| 64:04 | the seizure but it's been done to seizures. Yes. And it reduces |
|
| 64:09 | . And it is I mean it's , it's an approved drugs and we'll |
|
| 64:12 | at some of these studies at the end of this course. We talk |
|
| 64:17 | medical Canavan ours and we talk about pharmaceutical drugs and things that are in |
|
| 64:21 | market, you said fat molecules, is something that can go through tight |
|
| 64:28 | . So if somebody happening over accumulation fat intakes are there like this is |
|
| 64:38 | yeah, cholesterol accumulations cholesterol is a of the membranes. So there is |
|
| 64:46 | cholesterol levels. So actually when you high cholesterol levels and also high cholesterol |
|
| 64:52 | in the brain and that's an alter function too. Although it's not like |
|
| 64:58 | specific disease that stems from, you , high cholesterol levels in the plasma |
|
| 65:03 | . Were just starting to understand that . Good questions. Keep thinking, |
|
| 65:10 | the world what's happening and learning as progress in this course. This concludes |
|
| 65:18 | glia and we're gonna start talking about number and the trust we only have |
|
| 65:23 | little bit of time left today for . But the bottom line is that |
|
| 65:29 | are excitable membranes and all of the In the excitability action and the action |
|
| 65:37 | is happening at the level of the membrane on the outside of neuronal possible |
|
| 65:42 | is positively charged and inside is negatively . So if you were to call |
|
| 65:47 | outside ground environment cellular environment zero neutral , zero Miller bowls neutral charge were |
|
| 65:56 | sink an electorate inside the cell membrane that cell. We have a negative |
|
| 66:01 | to 65 year old. This is cell that is not very active. |
|
| 66:06 | we call this rustic membrane potential or address. And that's just the value |
|
| 66:12 | approximately negative $65 million. So the and the action potential occurs at the |
|
| 66:21 | membrane and to measure this deflection. change in the number of potential. |
|
| 66:28 | will need an amplifier and a volt . Now today, what we're gonna |
|
| 66:36 | is before we uh delve into the ionic distribution of sodium potassium florida and |
|
| 66:46 | across the plasma membrane. On the versus on the outside of the |
|
| 66:50 | How the channels to build the Arms law. You may want to |
|
| 66:56 | this for yourself. We're gonna talk nerds equation and Goldman equations here. |
|
| 67:04 | this is all coming. Next Not too glad. So, but |
|
| 67:10 | today I'm gonna talk to you briefly this circuit which is the knee jerk |
|
| 67:17 | fatale attendant circuit. And the reason is because action potentials need to be |
|
| 67:24 | fast. And the communication by motor in the spinal choir and the inter |
|
| 67:32 | in the spinal cord has to be fast in order to communicate that information |
|
| 67:37 | the muscles. So there could be muscular contraction. Okay now the muscular |
|
| 67:43 | potentials as I said are slower but of the action potentials produced by the |
|
| 67:48 | here are very fast and so this a good circuits to know and |
|
| 67:54 | Okay there are three types of cells are involved in the circuit. You |
|
| 67:59 | dorsal root ganglion cells you have inhibitory neurons and you have motor neuron cells |
|
| 68:09 | dorsal root ganglion cells and parents and are excitatory and they release glutamate into |
|
| 68:25 | are inhibitory cells local network and they glycerine. So the major inhibitory neurotransmitter |
|
| 68:35 | the spinal cord is glycerine. I telling you about Gaba in the brain |
|
| 68:41 | in the cerebrum and the C. . S. And in the spinal |
|
| 68:45 | proper Which is a part of cns exception is an inhibitory neurotransmitter. There |
|
| 68:52 | glycerine. Okay the dorsal root ganglion a pseudo unipolar cells which means that |
|
| 69:01 | gonna have the peripheral axon and essential on the inter neurons are multipolar |
|
| 69:11 | The motor neurons are key for They're gonna carry the information from the |
|
| 69:18 | cord into the muscles. They're also and they release a senal coding. |
|
| 69:32 | are also multipolar cells. So if were to activate this reflex. Are |
|
| 69:45 | recall. This is a typical test somebody may do when you visit a |
|
| 69:51 | office or even if you're doing a checkup sometimes the doctor will say sit |
|
| 69:57 | on the table or if you have problem with your leg or some pain |
|
| 70:00 | numbness or something, they may do . So this is a stimulus. |
|
| 70:07 | is a little mallet and that little will excite here. The muscle spindle |
|
| 70:15 | the quadriceps. This is a sensory from the quadriceps. Also with gangly |
|
| 70:22 | will carry that information. The ganglion be formed by the soldiers that are |
|
| 70:27 | outside spinal cord proper and the central that will innovate into the spinal cord |
|
| 70:34 | . And it will contact the motor and it will excite the motor neuron |
|
| 70:39 | this motor neuron through one synapse just synapse activating one motor neuron here will |
|
| 70:47 | acetylcholine and cause the contraction of the . For extensive muscle. So just |
|
| 70:53 | synapse is enough to cause the contraction this muscle. But if this muscle |
|
| 71:01 | the opposing muscle in order for you have the proper reflex on the |
|
| 71:06 | if this muscle contracted but the opposing hamstring is also contracted, this light |
|
| 71:12 | not going to move properly. So there is excitation here and there's a |
|
| 71:19 | of the quadriceps the same sensory neuron inform the inhibitory interneuron which is the |
|
| 71:26 | inhibitor in general and that inhibitor inter will inhibit the motor neuron and we'll |
|
| 71:32 | this motor neuron quiet and by keeping opposing muscle motor neuron quiet this muscle |
|
| 71:39 | going to be really Braxton is going be a proper kick response to the |
|
| 71:45 | . This is reflex. So you're controlling that. You cannot sit there |
|
| 71:50 | say I'm not gonna kick my life somebody put some out of your leg |
|
| 71:53 | going to go up. Yes. no no. That's inside the that's |
|
| 72:04 | nerve endings inside the muscle fibers that sensing the actual mechanical stimulus here and |
|
| 72:13 | that information to the spinal cord. that's about the that's what the that's |
|
| 72:17 | the peripheral axons that are projected into muscles into the skin into the tendency |
|
| 72:24 | cut the stimulus and carrying that information the reflexive responses to pick up the |
|
| 72:31 | . Yeah. Yeah. So this referred to simple reflex. Uh And |
|
| 72:46 | is a simple reflux because it can only mama synaptic one synapse sensory to |
|
| 72:53 | , one sensory one synapse activated Uh In reality it's actually at least |
|
| 73:01 | synopsis or three if you want to and the fact that reflex but it's |
|
| 73:06 | , efficient enough to contract this muscle synapse, it's not efficient to relax |
|
| 73:12 | also you have to involve the other . And then this is a very |
|
| 73:17 | type of reflex. And then we very complex reflexes. So for example |
|
| 73:22 | gagging reflex when there's something nauseous or some some nauseous stimuli or something that |
|
| 73:29 | around you. The gagging reflex That's very complex reflex that involves policy synaptic |
|
| 73:34 | and multiple members. But these are questions for the exam. You know |
|
| 73:39 | ? Because there's three subtypes of We talked about the morphological distinctions pseudo |
|
| 73:47 | versus multipolar, the neurotransmitters, the excitatory versus inhibitory in this case uh |
|
| 73:56 | seen as the inhibitor neurotransmitter versus Yeah. And this is why you |
|
| 74:02 | really fast action potentials because when you on the nail you shouldn't think for |
|
| 74:08 | two minutes. Should I step off now? No I think it |
|
| 74:13 | No. Does it really your reaction immediate. It doesn't mean that you're |
|
| 74:19 | consciously aware of your reflexes. So your doctor's office and you stimulate your |
|
| 74:27 | tendon with a mallet, your leg up, it doesn't mean that you |
|
| 74:31 | know your leg just went up and just looking around the room not understanding |
|
| 74:36 | pursue. So that information is going travel and ascend up the spinal cord |
|
| 74:41 | going to inform the higher centers and conscious perception of what's happening and even |
|
| 74:47 | subsequent motor outfit. The initial when stepped off the nail is one |
|
| 74:52 | But then you're gonna go through a complex motor pattern. For example of |
|
| 74:57 | overtaking your shoe off wrapping it and on and that is obviously coming from |
|
| 75:03 | centers. Alright so we're gonna end today and when we come back, |
|
| 75:08 | gonna talk about how these fast action happen in neurons and motor neurons. |
|
| 75:14 | start discussing the biophysics of the Thank you. |
|
