| 00:02 | This is Lecture four neuroscience Monday Wednesday . And we're discussing that we left |
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| 00:11 | talking about excitatory and inhibitory inputs onto cells that these cells have to have |
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| 00:19 | anatomy. Dendrites, dendritic spines, densities and shapes of these ponds for |
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| 00:26 | to be functional. And that these neurons need to process often several 100 |
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| 00:33 | thousands of active excitatory and inhibitory synapses bombarding the south and trying to influence |
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| 00:41 | cells. Making the cell fire inhibitory quenching the activity in the south and |
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| 00:48 | it quiescent or silent. Okay, functional regions in cells that we discussed |
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| 00:56 | , integrative conduct. I'll regions and regions and review those. And then |
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| 01:02 | delve into the science of subtyping different . So how many subtypes of excitatory |
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| 01:11 | are there? How many subtypes of cells are there? How can we |
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| 01:17 | distinguishing that? This is one subtype the cell versus and none. And |
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| 01:22 | early methods of staining the cells. example, the Golgi stain that revealed |
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| 01:28 | process is already revealed that these cells look very different morphological and so we |
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| 01:35 | one of the ways that you can between some types of cells is whether |
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| 01:39 | you know polar pseudo unipolar bipolar multipolar cells and where they're located. |
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| 01:47 | that implies function. But we don't know exactly much about their function. |
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| 01:54 | with staining them. We know a about morphology but to know about the |
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| 02:01 | . You have to do what these are active. They produce action potentials |
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| 02:07 | release neurotransmitter. You have to record . So you have to record action |
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| 02:12 | , electrical potentials, Changes in chemical release, how that chemical travels |
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| 02:20 | the synapse and all of these And that is yet to come in |
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| 02:25 | . But Hodgkin and Huxley 1939 is published the first action potential. That's |
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| 02:30 | important in showing the membrane properties and and that also becomes important in distinguishing |
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| 02:38 | activity and patterns of action potentials and different subtypes of self. We then |
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| 02:48 | talking about this circuit here, so this stage I'm gonna switch to this |
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| 02:56 | over here and continue here. We about the structure called the hippocampus. |
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| 03:02 | highlighted several features of the structure said it's predominantly a three layer structure straddled |
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| 03:09 | Statham Perama, Dolla Stratum. Orients pyramidal will contain 90% of all of |
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| 03:16 | parameter all cells and there's gonna be few of the criminal cells located in |
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| 03:21 | and orients letters. We discussed the that hippocampus is a part of the |
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| 03:26 | system, its function, its semantic , memory formation, memory, |
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| 03:31 | as well as emotional processing and emotional as well. Hippocampus has these laboratory |
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| 03:40 | in it that parameter cells that are cells that means that their accents are |
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| 03:46 | to project out of the hippocampus into other area. For example, the |
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| 03:52 | final cortex that is very close to cameras and those parameter cells will communicate |
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| 03:58 | out of this area of hippocampus into other area of the brain that I |
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| 04:02 | mentioned, the enter cortex at the time. There is not much diversity |
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| 04:09 | the excitatory cell population. The only between these cells, they look the |
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| 04:15 | . They're excited, they released, produce the same patterns of action |
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| 04:20 | But some phenomenal cells contain and others not C. B. Positive contained |
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| 04:28 | , they don't contain killed indent. this is the intracellular markers that help |
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| 04:33 | distinguish between two subtypes of the excitatory . Otherwise they're almost identical except for |
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| 04:42 | intracellular markers. So intracellular markers are for showing the differences in these |
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| 04:50 | Also if you may, it's in way of functional expression of cellular marker |
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| 04:56 | sells capability to express a time is protein or anything chemical. However, |
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| 05:03 | diversity of the neuronal population And the diversity in the structure and the Hippocampus |
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| 05:13 | from the inhibitory cells. So these through 21 number of subtypes of cells |
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| 05:22 | inhibitory interneuron that means that they will Gaba and their internals. They're staying |
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| 05:29 | within the serpent but they don't have that's gonna project out into other parts |
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| 05:36 | the brain like the enter cortex therefore communication and their control is locally within |
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| 05:44 | serpent. Now some of these inhibit also live in the same layers and |
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| 05:52 | look the same. They're done drives example have this north and south pole |
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| 05:58 | they're excellent. Even project onto the locations of excitatory cells here, we're |
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| 06:04 | into from the perspective that these inhibitory will control and train and maybe even |
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| 06:11 | with these excitatory cells tell that the in the brain they will locally try |
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| 06:16 | shape the activity that comes out of hippocampus. So the only way you |
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| 06:23 | distinguish between two and four is one of them is a basket cell |
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| 06:29 | stands for PV which stands for providing . Another one is a basket cell |
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| 06:35 | it stands for CCK for two other in deep blue three you don't have |
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| 06:40 | remember providing and RCCK but what you to remember is the cells can be |
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| 06:45 | . They may even produce the same of action potentials of the same identical |
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| 06:51 | location. Target the same areas of cells but they don't produce slightly different |
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| 06:58 | markers. Therefore they should be distinguished different subtypes of cells. So now |
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| 07:07 | have morphology, we have location of cells. We know if they're excited |
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| 07:12 | inhibitory, we know if their projection or local into neurons. Now we |
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| 07:19 | to know what patterns of action potentials produce. So using modern electrophysiology techniques |
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| 07:28 | is called a patch clamp technique or patch clamp a lot of times. |
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| 07:35 | is depicted here is an unstained slides placed under infrared camera as I explained |
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| 07:43 | you using a set of democratic mirrors infrared cameras. We can visualize neurons |
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| 07:51 | stains. So you place a slice the brain under a microscope. You |
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| 07:56 | the neurons you advance with the micro . Micro electrodes. These are made |
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| 08:03 | borosilicate glass. Micro electrodes are connected circuits that you don't see and micro |
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| 08:12 | . The cell, the amateur is micro meters. The tip of this |
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| 08:16 | electrode is less than one micro You fabricate those with micro pullers. |
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| 08:24 | actually pull pieces of glass and you them and polish it so you have |
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| 08:29 | perfect tips. The inside of the is filled with the solution. Because |
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| 08:36 | you hope the cell patch onto the , that cytoplasmic environment of that cell |
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| 08:46 | to be very similar to what's in pipette because if it is not you're |
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| 08:50 | to kill the cell. So if a different ph it's a different osmolarity |
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| 08:57 | different composition on the composition than from inside of the cell. You won't |
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| 09:02 | able to make these recordings if you and you're good at making all of |
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| 09:08 | and you patch to cells and you to cells. And you propose a |
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| 09:14 | that I think that the cell on right is a parameter cell. So |
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| 09:19 | don't. No you don't you haven't the stain yet. You just visualize |
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| 09:22 | top picture here. You put an because it looks parameter shape. So |
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| 09:28 | guess this parameters should sell a patch cell I stimulated the cell. These |
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| 09:34 | typical electro physiological recordings where you inject current, you de polarize the cell |
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| 09:41 | and potential a little bit more positive , more positive current until you generate |
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| 09:48 | boom boom three action potentials. You more current and you generate boom boom |
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| 09:55 | boom boom boom boom boom, more potentials. So this tells you something |
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| 10:02 | stronger is the stimulus into the cell frequency and higher number of action potentials |
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| 10:09 | will evoke. So the strength of stimulus could be equated to the number |
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| 10:16 | the frequencies of the action potentials that produced. Now next to this parameter |
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| 10:22 | sell I suspect that this cell is phenomenal sell it's something else and I |
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| 10:28 | that it's interneuron inhibitor interneuron. It's close to the criminal cells to attach |
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| 10:34 | cell. What I did is I exactly the same stimulus, exact same |
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| 10:41 | injections and strengths as on the right with just a little bit of stronger |
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| 10:50 | . The same amount that you would here producing three action potentials. This |
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| 10:55 | response is a very high frequency of potentials and then more Curran current and |
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| 11:02 | goes even faster. The same A very different response. That means |
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| 11:09 | cells have two different response properties or properties, a membrane properties and they |
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| 11:17 | two different dialects. The language is action potential dialect is the pattern and |
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| 11:23 | of these action potentials that get produced when you have a stimulus as a |
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| 11:31 | . So once I finish this experiment it wasn't just recording action potentials. |
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| 11:37 | was a lot more difficult experiment. were inducing a seizure like activity in |
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| 11:45 | networks. Uh During the experiment this also contains a dye called neurobiology. |
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| 11:53 | this is another diet that we should to your collection. You already know |
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| 11:56 | stain which picks up a few pick up Golgi stain with all the |
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| 12:02 | you already know. This will We talked a little bit about like |
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| 12:07 | like H. R. P. peroxide dates and viruses. Now this |
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| 12:12 | called neurobiology. And so this is dye that you will have inside the |
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| 12:16 | inside this electorate where you have that that is very similar to the side |
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| 12:20 | plasma solution. And during the electrical during this experiment this dye will enter |
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| 12:28 | the cell. And neuro biotin is diet that stays inside the cell and |
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| 12:34 | similar to golgi stain in the sense it reveals an entire morphology of that |
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| 12:40 | all of the processes. The the optical dendrites that come off the |
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| 12:46 | of the Haram inal cell. The dendrites that come off the base of |
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| 12:51 | parameter will sell. This is in and white you have an axon that's |
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| 12:57 | down and it's actually coming out of hippocampus in that direction. Okay, |
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| 13:04 | after the experiment was finished I had physiological data from that experiment I processed |
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| 13:12 | stain and I used neural lucida which the digital version of camera lucida that |
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| 13:19 | alcohol used to reconstruct the morphology of cells. And if we were to |
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| 13:27 | this cell and this cell to the and we would say you know |
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| 13:32 | This is an O A lam cell seven. Right here, that was |
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| 13:37 | to parameter cell. The reviewers would you're missing something. So you |
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| 13:44 | you are telling us they look The morphology is different. The pattern |
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| 13:48 | action potential is different. What are missing? We're missing intracellular markers for |
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| 13:54 | . You do immuno history chemistry. is history chemistry because there's no antibody |
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| 13:59 | , meaning that you injected the dye you may have to take a few |
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| 14:03 | steps to reveal the structure the morphology these cells. But for these markers |
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| 14:11 | as privileged young men we've mentioned other markers like CCK said, you |
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| 14:16 | really need another names. You need and that's called immuno history chemistry. |
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| 14:23 | now your your antibody will have a for a specific molecule or specific receptor |
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| 14:31 | chemical in that cell. And the that pick up that antibody will also |
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| 14:37 | up the dye that's tagged on that . So we show that these cells |
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| 14:44 | was so mad. A statin and and positive self And we proved to |
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| 14:50 | reviewers that we recorded from these oh cells and from these parameter cells. |
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| 14:57 | that's what it took to in modern just 10 years ago or so to |
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| 15:04 | to the reviewers that you recorded from specific subtypes of into neurons. One |
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| 15:11 | excited yourself in the specific circuit in hippo cannibals all of these basically you |
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| 15:18 | think of multidisciplinary steps between chemistry and chemistry, electrophysiology, microscopy all of |
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| 15:26 | things together. It's called neuroscience. true. So if you were to |
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| 15:32 | attach off the cortex for example and is different from hippocampus. But what |
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| 15:40 | find in the in the cortex again find that there's a lot of parameter |
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| 15:45 | , excitatory projection cells and specific layers we'll talk about cortical layers later in |
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| 15:50 | course and the projection excited to resell they'll project to other parts of the |
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| 15:56 | and they're flanked by the inhibitor into within these local circles. Even in |
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| 16:03 | neocortex that means that again you have inhibitory cells releasing gaba that will control |
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| 16:10 | happens here local and what gets communicated the adjacent parts of the brain. |
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| 16:16 | you can imagine this that the whole of electrical behaviors of cortical neurons. |
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| 16:22 | is illustrated here comes from the inhibitory . These cells are called delayed stuttering |
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| 16:30 | they're delayed because you have to inject a bit of current and only with |
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| 16:35 | delay after staying with that stimulus that of current the cell response with patterns |
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| 16:42 | action potentials that are likened to So with pauses there are cells that |
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| 16:53 | delayed but once they are activated with delay, their pattern of action potentials |
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| 17:00 | nonstop as as long as there's stimulus and it starts firing action potential. |
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| 17:11 | guy is a bursting cell. This very fast firing cell at the beginning |
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| 17:23 | a burst and then it slows down goes dr and this is the real |
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| 17:34 | of neurons. It really is. can actually convert it in the lab |
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| 17:40 | action potentials into the sound. I think I have this video here. |
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| 17:50 | let me check real quick. I have it on this computer. So |
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| 18:00 | uh try to bring that video after day. But the point that I'm |
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| 18:06 | to get across is that these are different dialects I'll speak. This is |
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| 18:10 | different dialects. Languages actually potential. the diversity and processing in these vertical |
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| 18:17 | and the hippocampus come from these So imagine that that everything was just |
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| 18:22 | . But that that that that that that that that that that that that |
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| 18:25 | that that that so boring and so . Our thoughts are very complex. |
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| 18:33 | sensory external stimulations coming into our ears, noses, mild skin are |
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| 18:41 | complex meaning that become at different frequencies of light frequencies of sound. And |
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| 18:48 | need the cells with all of these capabilities to produce different frequencies to speak |
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| 18:54 | dialects in order to process all of complex sensor information and produce all of |
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| 19:01 | complex motor and intellectual output which still from motor capabilities uh as as as |
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| 19:10 | do. And so this is what setup looks like to do these |
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| 19:17 | It's another setup that I used as postdoc at George Mason University. So |
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| 19:23 | did my PhD at Louisiana State University Center in New Orleans and then I |
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| 19:32 | on to do my post doc. first postdoc was for a year and |
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| 19:36 | half at johns Hopkins University Mind and Institute which is in Baltimore Maryland. |
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| 19:43 | my second postdoc, my first kind my graduate work was about the development |
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| 19:49 | the visual system and the inhibitor and circuits. My first post doctoral work |
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| 19:55 | an extension of that. Looking on and visual circuits in the cortex. |
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| 20:02 | my second post out which was at Mason University which is in Fairfax Virginia |
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| 20:08 | half an hour south of D. . That was work that I started |
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| 20:12 | epilepsy and abnormal uh epileptic networks and subtypes of neurons and how they behave |
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| 20:21 | epilepsy and trying to come up with ways and controlling seizures, epilepsy and |
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| 20:27 | dysfunctions. And so this was one the setups that I used. And |
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| 20:32 | these micro electrodes that was showing to are connected to pre amplifiers. These |
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| 20:39 | amplifiers are held by a really sophisticated manipulators. They're sitting on the table |
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| 20:46 | is floated. That means that if moves on this table, it's the |
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| 20:52 | table moves, it's floated with So these uh basically vibration free tables |
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| 21:02 | you insert the lectures which is micro or pre amplifiers and the holders. |
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| 21:07 | wires coming out. There would be half of the room of equipment with |
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| 21:14 | amplifiers, monitors for what you're seeing the microscope screen processing, digital |
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| 21:23 | post processing data coming out also with delay. So it's a sophisticated setup |
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| 21:29 | takes about. If you're good on with experiments, it takes you about |
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| 21:35 | hour, an hour and a half set up And once you set |
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| 21:40 | you're probably on that chair for about hours. And then another good, |
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| 21:47 | know, 45 minutes to save all data and clean up and make sure |
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| 21:51 | this captain essentially sterile. It's not in the sense, it's not sitting |
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| 21:57 | in the hood or anything, but semi sterile alignment. So everything is |
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| 22:01 | dry washed out of hot water, can't use alcohol because it kills the |
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| 22:07 | and things like that. So that's what it takes. And so if |
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| 22:10 | do these kind of recordings, you out of equipment, you can grab |
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| 22:14 | cheap like a 10 and a patron the electrode, do another recording, |
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| 22:19 | stop and then you do that for , you know, 15, 20 |
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| 22:24 | and you kind of don't want to it anymore. It's it's difficult, |
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| 22:29 | difficult work. You know, you're to squeeze four lectures, five |
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| 22:34 | There's only a few lunatics like like in the world, we try to |
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| 22:37 | multiple we call multiple whole cell clamp recording simultaneously real time with imaging |
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| 22:43 | something like that. That's exactly what do. You know? And and |
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| 22:46 | and it's and it's difficult. Now kind of work can be done in |
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| 22:51 | too. So a whole animal. you know, you cannot you |
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| 22:57 | The in vivo work will be even if this is an hour, an |
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| 23:01 | and a half to prepare if you're with rats and viva. It could |
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| 23:05 | 23 hours to prepare if you're working high order species. It may take |
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| 23:11 | hours to prepare. Like you're real almost you're doing electrode implantation and things |
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| 23:16 | that. So it's all fun So Glia, let's talk about |
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| 23:26 | We started talking about Glee a little we actually already mentioned astrocytes uh which |
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| 23:33 | see here and we talked about astrocytes a part of the blood brain |
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| 23:38 | We said that they have these feet that part of the blood brain barrier |
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| 23:42 | they check one of the checkpoints to what happens what enters into the |
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| 23:49 | but leah for a long time. and greek Glia was thought to be |
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| 23:55 | of a glue of supporting function. that's no longer the case. We |
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| 24:01 | support and insulate neurons. But they're scavengers involving damage repair and cleanup. |
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| 24:11 | glia are the smallest and the most elements in the brain. And they |
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| 24:17 | activated with injury infection, inflammation. also involved in cytokine release and regulation |
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| 24:26 | these pro inflammatory cytokines and they get activated by the cytokine release. |
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| 24:32 | if you think about like macrophages in way and other parts of the |
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| 24:36 | but they're they're not macrophages, their glial cells. And when we talk |
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| 24:41 | these different subtypes of cells, I'm remind you briefly that you have in |
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| 24:49 | folder. Um let's keep like an out of this for a second. |
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| 24:58 | have in your folder, a lecture this uh supporting class lecture documents. |
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| 25:10 | for example, this is michael glial dynamics. So you can click on |
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| 25:17 | , apologize if there's some commercials in of these videos. Some of them |
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| 25:26 | especially, Okay, let's talk about in this video. This is this |
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| 25:42 | an injury that that basically is induced neural tissue, this wide blob here |
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| 25:51 | the cells that are stained, they're stained for micro Julia. So you |
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| 25:58 | see there's this time lapse here because , six hours, 30 eight |
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| 26:08 | So we're looking at a time lapse ours, right. And so this |
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| 26:15 | the beginning of the video. You the injury. You have the injury |
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| 26:25 | and look what happens within minutes to . You have microbial selves. These |
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| 26:32 | microbial cells that start extending themselves their processes because that's what's labeled polar, |
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| 26:39 | site of the injury and that And you actually are even seeing there |
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| 26:47 | much, start moving through space closer the side of the injury. So |
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| 26:55 | glial cells, if there is there will be a part of the |
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| 27:02 | and repair clean up of the Maybe if that's uh an injury that |
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| 27:09 | bursted or something uh like a shrapnel the brain or uh something to do |
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| 27:17 | death of neurons. So michael glial will rush in and start taking care |
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| 27:24 | that environment, start generating inflammation around inflammation will call upon immune response |
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| 27:31 | So there's sort of run in between cleanup, inflammation and immune response that |
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| 27:37 | would see in the brain. They also get activated with infections. |
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| 27:43 | So that's michael glial cells. What's on our slide astrocytes and we'll come |
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| 27:53 | and talk more about astrocytes. But a long time astrocytes were referred to |
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| 27:58 | housekeeping chores, neurotransmitter and ion update astrocytes actually regulate the amount of |
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| 28:05 | So astrocytes can regulate the amount of that is synthesized by synthesized an amount |
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| 28:11 | glutamate that is available for the excitatory ergic neurons to release by that |
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| 28:17 | So you learn about that very much in synaptic transmission synaptic control regulation of |
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| 28:25 | excitatory neurotransmitter, the major inside of neurotransmitter in the brain production, exercise |
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| 28:32 | also involved in blood brain barrier. the song about talk to the blood |
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| 28:40 | they monitor what neurons are doing, they're communicating to each other and regulating |
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| 28:46 | means of their communication. Which is neurotransmitter production you have during early |
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| 28:54 | neurons are born in specific parts of brain. We don't have time to |
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| 29:00 | over those areas of the brain that responsible for the birth of new neurons |
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| 29:06 | there's few areas in the brain and those areas neurons migrate. That means |
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| 29:12 | they're neuron that is in the occipital . Was not born in the exhibit |
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| 29:17 | lobe. It was born somewhere in of these special zones inside the brain |
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| 29:24 | generates your neurons. And then new that have to migrate and find their |
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| 29:30 | to their address to their town which a circuit to their street, to |
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| 29:38 | house, their mailbox, which is specific location and some circuit which is |
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| 29:44 | neighborhood which is a city. so you have radial glia that is |
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| 29:51 | involved in the migration of neurons and interesting phenomenon that happens here sounds interesting |
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| 30:08 | . So um this is really This is a neuron that is migrating |
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| 30:17 | what this neuron is doing, its cytoplasmic, nearly continuous cida plaza becomes |
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| 30:27 | its membrane becomes continuous with radial real during early development. And it uses |
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| 30:34 | real style as a ladder sort of a rope or a lattice to climb |
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| 30:42 | find its correct location in the So this is what's happening when you |
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| 30:48 | the formation of different brain circuits and talk about the development, early development |
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| 30:53 | the primary and secondary testicle formation and the precise circuit formation in the |
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| 31:02 | Okay, so there's another one that in general uh neuronal chain migration. |
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| 31:13 | is without radial glial cells. But is what is happening when the cells |
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| 31:20 | finding their final destination circuits areas. mailboxes where they're gonna stay is that |
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| 31:28 | a lot of migration and they become and cytoplasm continuous for a period of |
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| 31:36 | until the separate off each other. so you'll have radio glial cells that |
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| 31:43 | very much involved in aiding guiding this migration and also potentially serving as a |
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| 31:52 | to some of the microcircuits that form the new cortex. Especially because there's |
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| 31:59 | so many radio glial cells, so lattices and so many circuits eventually microcircuits |
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| 32:06 | form in our adult mature brains. , next we have growth factor releases |
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| 32:14 | of their functions so they release these that are called also neurotrophic factors. |
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| 32:22 | they're involved in longer processes that are involved in fast cellular communication involved in |
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| 32:28 | processes and repair processes but they can influence the release of slow growth factors |
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| 32:39 | astrocytes again this blood brain barrier will back to it in general glia and |
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| 32:46 | passively actively control synaptic genesis genesis or of new synopsis. The birth of |
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| 32:52 | synopsis. The number of the the strength of function of the synopsis |
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| 32:58 | the efficacy for plasticity of the synopsis well. So very much intricately involved |
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| 33:05 | regulating these processes. But they do differently neurons fire action potentials. Glia |
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| 33:12 | not fire action potentials. So when said that there are two excitable types |
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| 33:18 | tissues, neuronal and muscle. Lien not excitable in the sense of producing |
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| 33:25 | potentials. It has a potential and communicates with much slower calcium potentials or |
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| 33:34 | waves. So they don't produce these fast 12 millisecond action potentials. The |
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| 33:40 | dialect that we talked about that neurons . They have a different language. |
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| 33:45 | very slow, it's much slower than potentials. It's a slower language. |
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| 33:50 | in general you can think of as are involved in this fast synaptic transmission |
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| 33:57 | release finding posson, attic response action . Well Glee are operating at a |
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| 34:04 | slower temporal scales and they're regulating the calcium levels, overall neurotransmitter levels and |
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| 34:14 | other processes like inflammation and neuron immune slower processes. So but actively involved |
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| 34:24 | course and everything that the brain is does A ligo Deandra sites in the |
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| 34:33 | . N. S. Form myelin so a ligo dender sites will have |
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| 34:39 | multiple processes and feet coming off and one of these processes becomes a segment |
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| 34:48 | violent segment on an axon And axons have multiple segments and each one of |
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| 34:55 | segments is contributed by one arm from legal tender sides in the cns and |
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| 35:01 | peripheral nervous system. And the N. S. You have Schwan |
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| 35:06 | . It's a different subtype of Leo that is responsible for my elimination. |
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| 35:12 | each one of the segments here is separate Schwan South with its own nucleus |
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| 35:19 | between Myelin segments. You have what called nodes of wrong dear. And |
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| 35:26 | when neurons produce the action potential, does not influence that action potential beyond |
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| 35:37 | it, insulating the accent so that neurons can produce reproduce an action potential |
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| 35:45 | each note of ranveer. And when action potential reaches the accidental terminal would |
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| 35:51 | the same amplitude and properties as it when it was started at the |
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| 36:08 | This is my elimination. We already at my elimination. We look at |
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| 36:11 | cross section of the axon. We the sheets that are wound up |
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| 36:17 | Okay, and this is the note round there again, you'll have mitochondria |
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| 36:21 | in there and you'll have specific subset sodium and potassium channels that are going |
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| 36:28 | be able to reproduce the action potential conduct it to its distal locations. |
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| 36:35 | , those membrane channels. Is that physiologically demarcates, what is gonna be |
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| 36:42 | how does it know to stop growing finalization here. How how does the |
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| 36:47 | know how to stop the segment and it's wrapping around. That's a great |
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| 36:52 | . A lot of it has to with cell and self communication and markers |
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| 36:56 | and and binding. And it's a question because it has to be properly |
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| 37:02 | because if it's not properly recognized or you don't have a proper Myelin |
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| 37:06 | you will have essentially a wire that's insulated. And what happens is the |
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| 37:12 | will be leaking. So now how the cell know when to stop? |
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| 37:17 | has in the liquid emphasize. It obviously on the size of the |
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| 37:22 | So it's by night it doesn't you , it's not like either one millimeter |
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| 37:27 | either 10, 1 micro meter or micro meters. You know, it's |
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| 37:32 | one to a couple of micro And so you have that anatomy that's |
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| 37:37 | from a liberal emphasize cell to cell of the markers that tells us that |
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| 37:44 | area is to be insulated in this has channels like potassium sodium channels and |
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| 37:49 | not to be insulated. That's my answer. Although the precise science of |
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| 37:54 | , I don't have in my Very good question. Uh and it |
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| 37:59 | leads us into the next slide that about Myelin dysfunctions. What can happen |
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| 38:06 | Myelin dysfunction. This Myelin as we're about Myelin and it's wrapping around, |
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| 38:13 | really compaction. That's what you're doing you're wrapping around, wrapping around and |
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| 38:19 | the myelin? And there are seven , Seven related proteins. This is |
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| 38:27 | example, Myelin associated lack of seven proteins involved in allowing for that |
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| 38:36 | . So there's, like I there's a cell to cell recognition or |
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| 38:40 | Signals and in this case you have proteins and there's a certain number of |
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| 38:45 | proteins and certain expression levels of these that will determine and regulate the proper |
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| 38:51 | of this model. This is Maggie just one of the examples of the |
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| 38:57 | um Now on top I have here from lightest inflammation and D. Myelin |
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| 39:05 | ? You actually can cause infection in brain and that infection can cause d |
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| 39:14 | Nation. So with instructions you can the Myelin Nation, I then mentioned |
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| 39:23 | diseases charlotte marry tooth disease will come to that and we'll mention the second |
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| 39:28 | PMP 22 there and multiple sclerosis. there's two more diseases that we're adding |
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| 39:37 | . Multiple sclerosis is an auto immune . This is a disorder where your |
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| 39:46 | starts thinking that your myelin is your and actually starts destroying itself and Miles |
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| 39:54 | multiple sclerosis again, what is the ? What are we gonna learn about |
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| 40:01 | sclerosis? You have a dim Allan . When does it occur? Is |
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| 40:06 | a developmental disorder? Or is it aging condition? When is a typical |
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| 40:13 | M. S. multiple sclerosis in 30's 30s and the 40s. |
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| 40:20 | Not development on this one that's important disorder. That means your body is |
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| 40:29 | your own myelin in this case It's to chromosome 18. It's linked to |
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| 40:36 | chromosomes. That this is one of mutations that has to be recessive. |
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| 40:41 | bad. Ah leal's that ends up D. Myelin nation. What is |
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| 40:47 | my elimination? My elimination is pathology a symptomology with the symptomology of multiple |
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| 40:55 | . It really depends where the Myelin happens. You have my eliminated axons |
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| 41:01 | C. N. S. In areas of process emotions, memory, |
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| 41:05 | function or you have the Myelin Nation is global to very small extent. |
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| 41:12 | you're slightly losing a lot of different . Just becoming less and less ability |
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| 41:18 | those different functions. So the tremors convulsions would be one of the motor |
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| 41:26 | that you would see. Especially at or uncontrollable cases of multiple sclerosis. |
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| 41:33 | there's other symptoms, there's pain, an ability to walk if you have |
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| 41:38 | Myelin Nation in your legs or the and the spinal cord there's many different |
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| 41:43 | that M. S. Can And quite often the first episode of |
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| 41:48 | mess comes from nowhere literally you stand from the bed and you cannot walk |
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| 41:54 | you say what and you know you to hospital and and their their their |
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| 42:01 | in presenting this D. Modeling Um and there are models by which |
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| 42:08 | can study this demand pollination. So is obviously if you can do this |
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| 42:14 | infections or injections of chemicals you can . Myelin eight or you can have |
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| 42:20 | genetic mutation. So you inject something in fact the brain with something that |
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| 42:30 | a virus that will start causing eating off the myelin or in this case |
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| 42:38 | animals that have a genetic mutation that called transgenic. There's been some change |
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| 42:47 | their genes. So a lot of scientists would discover From a so 19 |
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| 42:54 | animals that is causing the myelin And then you would have transgenic animal |
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| 43:00 | and you can have a mutant that have the recessive mutation and it will |
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| 43:07 | a shiver. This is a shiver mouse. And it basically is what |
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| 43:14 | modeling the tremors and some convulsions that would observed in humans. So animal |
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| 43:22 | as a model that you want to and replicate as much of the human |
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| 43:28 | as you possibly can. It's genetic on chromosome 18. You want to |
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| 43:32 | chromosome 18. If the mechanism of is the myelin nation, you want |
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| 43:37 | see the myelin nation. If the is tremors and convulsions, you want |
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| 43:41 | see tremors and convulsions right? So is what is real when you talk |
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| 43:46 | animal models. It's not just a that you're using as a model. |
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| 43:51 | a whole sequence in the special in animals. So now you have this |
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| 43:57 | mutant that has scant or almost no Nation with this symptomology. And in |
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| 44:05 | experiment it's actually a trance faction with genes and normal gene gets reintroduced into |
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| 44:13 | animal. And with this gene therapy you may experimental trance faction with this |
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| 44:22 | now you have more of the myelin produced and you can restore and improve |
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| 44:29 | of the Myelin Nation. And so pharmaceutical drugs for human conditions would try |
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| 44:36 | stop the D. Myelin Nation. I don't think there's anything that rebuilds |
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| 44:42 | myelin but slows down the progression fairly in the pharmaceutical world. Charcot Marie |
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| 44:52 | disease is also a myelin dysfunction. this is precisely why I said you |
|
| 44:58 | to start developing a little bit of clinical language. It is a developmental |
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| 45:05 | In this case it's a different It's too much of PMP 22 protein |
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| 45:10 | gets produced, It would have chromosome . It's a different uh genetic code |
|
| 45:20 | is basically at fault. Here. have gene duplication, too much of |
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| 45:25 | to which you can stand for. you can see you have a normal |
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| 45:30 | ated axon and this is in the , peripheral PMP too. So |
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| 45:39 | S. Is C. M. . Mostly this is peripheral disease and |
|
| 45:46 | you have is developmentally if you don't shark ordinary tooth. Do you have |
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| 45:53 | D. Myelin Nation? If you the Myelin Nation that means you cannot |
|
| 45:59 | in the nerve showing from the spinal you cannot produce proper electrical signals. |
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| 46:05 | you don't produce proper electrical signals you contract your limbs properly. If you're |
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| 46:13 | your bones are soft your muscles are . If you're not contracting your limbs |
|
| 46:18 | you can end up with these bodily and so if it's detected early enough |
|
| 46:25 | only way to treat this really is braces and uh physical therapy. But |
|
| 46:36 | people still and that may be having gate issues, balance issues. Even |
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| 46:42 | if they're detected early with this disease treated early you know now you can |
|
| 46:48 | how de milo nation can cause a which is also in you or you |
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| 46:53 | this developmental Charcot Marie tooth disorder in periphery. You know again great exam |
|
| 47:03 | . This sort of puts the the image a lot of the players that |
|
| 47:10 | talked about into one image. You the most dynamic elements of micro glial |
|
| 47:18 | . We talked about have the legal sides, insulating neurons, you have |
|
| 47:27 | and you can see astrocytes there in business here in the synopsis and they're |
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| 47:32 | on the capillaries here. The end as a part of the blood brain |
|
| 47:38 | . Remember we talked about how these and neurons have ace two receptors. |
|
| 47:43 | if you breach this blood brain barrier covid 19 can in fact the astrocytes |
|
| 47:50 | neurons because they will have these two you have these append um All cells |
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| 47:58 | cells are separating the super spinal fluid sort of a cell layer from the |
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| 48:03 | space and the fluids that are surrounding cells immediately. And there is a |
|
| 48:09 | that dependable cells could even be like cells, stem glial cells that can |
|
| 48:15 | real cells too. So it's a image to kind of keep in mind |
|
| 48:21 | you remember different functions of neurons. is a repeat image that we already |
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| 48:26 | at again. This is your blood . And you have a lot of |
|
| 48:32 | capitalism micro vascular ization in the So the nearest basically there's so many |
|
| 48:43 | in the brain that the distance the distance between the two capillaries is only |
|
| 48:49 | micrometers apart only five selma's apart from capillaries and the blood supply. Why |
|
| 48:58 | it so important because blood carries And we talked about how neurons need |
|
| 49:06 | to eat a lot of glucose. need a lot of uh dietary intake |
|
| 49:13 | , they need a lot of T. P. They need a |
|
| 49:16 | of oxygen. So you have to proper oxygenation. You have to have |
|
| 49:22 | exchange of oxygenated blood deoxygenated flow of blood arteries, veins, the circuits |
|
| 49:32 | have to protect the circuit. So one of my favorite structures anatomically and |
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| 49:38 | whole body is called the circle of . And it's this vascular circle that |
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| 49:44 | in the seat of your brain. if one input is compromised, the |
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| 49:51 | can supply this part of the brain the circle through the other inputs carrying |
|
| 49:56 | into the circle. There's protection redundancy there's control of what passes into the |
|
| 50:05 | . You have tight junctions that are between the and epithelial cells. Types |
|
| 50:12 | are types that means they don't let through. And things that pass through |
|
| 50:17 | blood brain barrier are important. Things nutrients are molecules. A lot of |
|
| 50:23 | will have transporters or facilitators. A of them will be welcome to pass |
|
| 50:28 | based on their sides. Which is very important. A lot of them |
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| 50:33 | be welcomed based on their cell That's all your ability. Member insoluble |
|
| 50:43 | . You have the parasites. You these uh and feet of the |
|
| 50:51 | Astrocytes glial processes astrid palaces process that patrolling very tightly controlling also with gets |
|
| 50:59 | the brain. So blood brain It's a great thing because whatever you |
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| 51:07 | just goes into your stomach, goes your blood. Whatever you inhale goes |
|
| 51:18 | your lungs, goes into your If you have some fancy transdermal creams |
|
| 51:27 | put it on your skin it goes the blood, doesn't go into the |
|
| 51:35 | Now from the blood things get delivered the brain, right? You have |
|
| 51:40 | headache, You take an Advil and will go into your stomach digestive gastric |
|
| 51:50 | into the digestive tract micro village suck up and that 200 mg of ibuprofen |
|
| 51:59 | much of it is in the I don't know I haven't done the |
|
| 52:04 | . K. By availability studies on brand name or target name. |
|
| 52:10 | I don't know. But a small of it gets into your blood. |
|
| 52:16 | then what happens? What if you a really strong headache? But if |
|
| 52:22 | have a big problem but if you a neurological problem, what do you |
|
| 52:25 | migrants, what if you have You again swallow pills. Most of |
|
| 52:31 | things that are therapeutic that we treat or swallowing pills. Uh you don't |
|
| 52:38 | much injections into veins at home when have a headache and you don't have |
|
| 52:43 | nasal spray ice. Remember this is pathway of entering into the brain. |
|
| 52:49 | just for viruses but also for And you have some inhalers when you're |
|
| 52:55 | about lung problems and and asthma but it's the stuff that gets into the |
|
| 53:00 | . A fraction of that stuff it drops into your stomach gets into the |
|
| 53:06 | and now it has to get into brain. So it's great because you |
|
| 53:11 | on a daily basis we consume substances , we drink something, there's a |
|
| 53:16 | of potassium or something and not all it is just really passing into the |
|
| 53:21 | . You have this checkpoints that are it. However if you compromise the |
|
| 53:30 | brain barrier stuff can start getting in you have information if you have |
|
| 53:35 | if you have viral infection as we , you disrupt these tight junctions. |
|
| 53:41 | the blood brain barrier becomes leaky? means things from the blood vessels, |
|
| 53:46 | can leak in the substances that are supposed to be can pass through these |
|
| 53:51 | junctions but can pass into CMS. other issue with blood burn barrier for |
|
| 53:59 | protective functions. It's terrific and fantastic for treating brain diseases and neurological disorders |
|
| 54:07 | a barrier because as I explained to most of the things that swallows the |
|
| 54:13 | goes into your blood. If you're the hospital situation you're getting I. |
|
| 54:19 | . Injections maybe of some drugs. I'm getting at is do you have |
|
| 54:26 | severe seizure? You have a severe ? If you take some medication there's |
|
| 54:31 | aspects that we deal with medications. long is it gonna take for it |
|
| 54:35 | get digested to get into the how much of it is going to |
|
| 54:40 | into blushing, how much of it gonna pass into the brain. So |
|
| 54:45 | of that 200 mg of ibuprofen. don't know how much ends up in |
|
| 54:49 | brain. Again I didn't do those but it's safe to assume it's a |
|
| 54:52 | , it's a small fraction of that of the active ingredient that enters enters |
|
| 54:58 | the brain and blood and then eventually into the brain. So if you |
|
| 55:06 | to design a really good neuro drug have to think about blood brain |
|
| 55:13 | what would be good features of the drug if you have to swallow |
|
| 55:19 | or should I design a drug that can spread, where is it going |
|
| 55:24 | go from the nasal epithelium? I'm just get stuck there and get |
|
| 55:29 | And my problem is in the occipital , you know, all of these |
|
| 55:34 | you have to start thinking about, what neuro pharmacology is, It's not |
|
| 55:38 | what substances buying to, what what effect they have in the |
|
| 55:42 | but actually how do you design a ? What are the features of the |
|
| 55:47 | in that drug? It has to small. Obviously, if you want |
|
| 55:52 | just something to pass, you so maybe it's nano, you're looking |
|
| 55:55 | some nanotechnologies, maybe it has to lipid soluble so that once it's in |
|
| 56:01 | blood and boom, can cross through lipid membranes or maybe you can find |
|
| 56:07 | that can take advantage of some transporters here and tag it so that |
|
| 56:13 | you fold the transporter and you hey, the transporter thinks you're, |
|
| 56:18 | know, something else and it's bait switch, you are something else. |
|
| 56:23 | know, So this is blood brain , it's a, it's a gift |
|
| 56:27 | us, but it's also a challenge it's also a challenge in neuro pharmacology |
|
| 56:33 | from any drug development perspective, this what you have to think about is |
|
| 56:38 | to deliver drugs effectively into the brain beyond that do you want the drug |
|
| 56:45 | in the brain? Everything that goes your system into your blood, it's |
|
| 56:48 | to say it's everywhere in your It doesn't mean it's gonna be and |
|
| 56:52 | everywhere in the brain because it may specific receptors that it binds to that |
|
| 56:57 | only found in specific parts of the . But the whole point is that |
|
| 57:01 | want to design the future drugs that easily passing through the blood brain |
|
| 57:05 | You can control the passage easily and can target specific subtypes of the cells |
|
| 57:11 | we talked about. We don't want make the whole room silent and no |
|
| 57:17 | . We want to take out the dialect players and have the cells function |
|
| 57:24 | again. So this is the ultimate how to get the drugs to sell |
|
| 57:29 | subtypes and specific circuits in the brain a question answered it good. So |
|
| 57:39 | think this is the last slide Thank you very much for being |
|
| 57:43 | Will be happy to take any Yeah, capped. Ations. Gap |
|
| 57:59 | are gap junctions. So hang on that question because we'll talk about gap |
|
| 58:03 | will talk about neural transmission. Gap are electrical synapses between yourselves. We'll |
|
| 58:08 | back to that. Good question. , so don't come here on monday |
|
| 58:16 | it's labor Day and I will not here and I hope everybody goes |
|
| 58:20 | So I'll see you back here in week on Wednesday? Will there be |
|
| 58:30 | review |
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