| 00:02 | Welcome back. This is neuroscience lecture . Would we discussed last time where |
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| 00:08 | of the features of the cells the to find the neurons. Some of |
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| 00:12 | things that are basic in common amongst lot of different cells in the body |
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| 00:17 | some of the things that are unique as modern nations such as accent, |
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| 00:22 | segment accident initial Hillock which produces the potential. You have a zonal terminals |
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| 00:28 | you have electrochemical synaptic neural transmission that place there. You have these very |
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| 00:35 | in very spines that are little outgrows the gun rights. We discussed that |
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| 00:41 | have the same machinery for genetic expression that different cells and different parts of |
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| 00:47 | body and different subtypes of neurons in brain expressed slightly different subtypes of genes |
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| 00:53 | smooth in the plasma particular um and apparatus with their respective functions, |
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| 00:59 | which is a source of energy in form of ATP and the brain consumes |
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| 01:04 | lot of energy. The fasting lipid layer plasma membrane, which is really |
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| 01:08 | fluid mosaic. Model mosaic is comprised different elements on the different parts of |
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| 01:14 | plasma membrane or trans membrane elements such receptor channels, receptor length of G |
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| 01:21 | coupled receptors like a proteins, And it's fluid because it's not just |
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| 01:27 | by fluid. It's also the fact the mosaic itself rearranges and these elements |
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| 01:32 | their trance membrane elements have ability to dynamic and to move through these fossil |
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| 01:37 | bi layer as it is demanded by in the underlying structure of the membrane |
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| 01:44 | the overall structure of the cell is by the side of skeletal elements. |
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| 01:49 | tubules, narrow filaments and micro Micro tubules being the largest ones and |
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| 01:56 | these micro tubular highways. Um This a mile in sheep that has shown |
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| 02:02 | surrounds the axon and acting molecules being smallest ones. And because active molecules |
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| 02:08 | the smallest ones will also find most the active elements located on the |
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| 02:16 | close to the outer edges of the membrane responsible for shaping. Really the |
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| 02:21 | edges of the cell membrane and other like turbulent, which is stand in |
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| 02:27 | here will be located closer to the . Uh not only the solo but |
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| 02:34 | nucleus of the south supporting the base and larger side of skeletal elements |
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| 02:41 | So active molecules have the ability to arise and to longer change some deep |
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| 02:46 | arise and get broken up into shorter . And all of this is necessary |
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| 02:51 | order to change the shape of the brain. Especially when you're talking about |
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| 02:56 | good expires which are very small and changes in the scrum brain scan can |
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| 03:01 | very significant to the synapse. So Alzheimer's disease pathology hallmarks of this pathology |
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| 03:10 | shared the slide. We said that the extra cellular outside environment of the |
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| 03:15 | you have the formation of the amyloid amyloid. See now Alzheimer's plaques, |
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| 03:21 | start aggregating calcify ng and impinge ng disrupting the connectivity between the south and |
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| 03:27 | networks at least south and also preventing action potentials to be normally generated by |
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| 03:34 | Exxon initial segments of accidents in So on the inside the neurons liberally |
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| 03:41 | which are associated with another protein. haven't discussed tile Prodan, the neuro |
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| 03:47 | tangles that we discussed. They will with a normal transport inside the south |
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| 03:53 | delivery of goods and stuff. So have an extra cellular clock and you |
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| 03:57 | an interest are tangled on the gross pathological pathology. You would see a |
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| 04:05 | Alzheimer's pathology of Alzheimer's pathology or severe of gray matter mm white matter, |
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| 04:12 | neuro degeneration, significant narrative generation with cortex of the neocortex and also higher |
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| 04:19 | structures. Right? We also talked symptomology. So if you remember at |
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| 04:24 | early stages we said that person may short term memory loss may be a |
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| 04:31 | bit of disorientation, anxiety and then becomes plaques in the severe form of |
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| 04:36 | takes over. It becomes deadly to functions of the brain which controls vital |
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| 04:42 | of the body. We talked about onset of the disease and we said |
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| 04:46 | this is an aging persons disease. is not a normal part of |
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| 04:51 | There is a high prevalence of that starting 50 and older and the older |
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| 04:56 | are 80 and 90. The higher likelihood is a person having or developing |
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| 05:02 | disease. We didn't talk that much therapy but we did talk about how |
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| 05:08 | come back and talk about therapy and mentioned that most of the drugs that |
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| 05:12 | treat acetylcholine dysfunction. And so this a network and the neuro transmission. |
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| 05:19 | your transmission that gets impaired in Alzheimer's significantly and early on uh you have |
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| 05:27 | have a proper synaptic transmission in order the cells to communicate. And so |
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| 05:31 | you have a breakdown of either intracellular cellular early by the plaques or by |
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| 05:36 | tangles of the synaptic transmission or deliver goods along the accident, they will |
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| 05:42 | the communication between neurons and the communication networks. But once an action potential |
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| 05:49 | produced in this accident initial segment here is actually regenerated at the nose of |
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| 05:54 | D. Polarizes external terminal which is loaded with mitochondria is to have significant |
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| 06:00 | of energy source of A. P. And it has all of |
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| 06:04 | vesicles that are sitting on the plasma . The synaptic vesicles will fuse with |
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| 06:10 | plasma membrane. The release chemical neurotransmitter the synaptic collapse the physical space of |
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| 06:16 | 20 nanometers that are supporting the pre . There are past synaptic neuron and |
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| 06:22 | an optically we already know that we'll densities of pa synaptic receptor. So |
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| 06:27 | these pots synaptic receptors for glutamate and synapse or the action the has vesicles |
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| 06:33 | glutamate is an excited person up if vesicles contained Yabba Yammer community uric acid |
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| 06:39 | it contains Gaba receptors, parson that effect is going to be inhibitor |
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| 06:44 | the boston opportunity. So glutamate will posttraumatic mirror and will make it more |
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| 06:50 | , will make it more likely to an action potential and inhibit. There |
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| 06:54 | analysis will make this fast synaptic neuron likely the fire an action potential to |
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| 07:01 | the information to the interconnected regions. have interrogated transport and retrograde transport. |
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| 07:09 | we briefly discussed as uh Ineson is transport and dina and has a retrograde |
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| 07:16 | . So goods go both directions from settlement to the periphery into the processes |
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| 07:21 | from the processes into the summer which the retrograde transport. And we talked |
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| 07:27 | you can use the retrograde transport or such as the horseradish for oxidants in |
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| 07:32 | if you want to for example, what uh neurons are connected to this |
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| 07:39 | of the periphery or this patch of brain. If you're interested in the |
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| 07:43 | or nerve you can inject horse peroxide itself will get taken up by |
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| 07:48 | accidents that will get transported retrograde lip the selma's of these nerve cells and |
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| 07:53 | will precisely know what network of cells which cells which neurons are connected to |
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| 08:00 | particular patch off the brain or of scan and so on. Herpes virus |
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| 08:06 | rabies, viruses will also use retrograde and some of the viruses be capable |
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| 08:11 | both interrogate and retrograde transport. We about in good experience and how they |
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| 08:17 | in many different shapes on the in to that they also contain colorado so |
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| 08:21 | complexes and also their own stores of which makes them biochemical independent. These |
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| 08:27 | by units are biochemical independent of this than riddick shaft or the overall summer |
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| 08:34 | the cell, which is really responsible generating most of the goods coding for |
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| 08:39 | of the goods with respect to fragile . It's an autism spectrum disorder. |
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| 08:46 | we talked about Alzheimer's disease, we mentioned something that is called co morbidity |
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| 08:52 | is something that will make you die because you have the disease. For |
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| 08:58 | , if you're disoriented and you fall you break your bone now you have |
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| 09:01 | broken hip, you have a potential mobility that has developed in addition to |
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| 09:07 | disease and now you're even more likely follow and injure yourself again. Therefore |
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| 09:14 | lifespan is getting shortened by these comorbidities fragile like syndrome. Uh One of |
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| 09:21 | comorbidities is apple, etc. And . And unlike alzheimer's disease, this |
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| 09:27 | a developmental disorder. So abnormal formation the spines, abnormal densities. Uh |
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| 09:35 | length of these spines and location along shaft will resolve the mental did |
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| 09:42 | So as a model essentially for precise and the dendritic spines and fragile |
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| 09:49 | That's a developmental disorder. And like disease. So the prevalence would be |
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| 09:55 | answer and uh this is as much we're going to touch on this |
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| 10:02 | But to take our message is how uh dendritic uh connections that expands in |
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| 10:11 | and how if you disrupt this precise of the explains what is happening. |
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| 10:22 | I can never kept that open on . And as an example on the |
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| 10:33 | you have a cell where you have of the excitatory synopsis shown in |
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| 10:38 | It contains glutamate receptors. Blue are agree dramaturgical excitatory synopsis. All of |
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| 10:44 | orange synopsis. Gaba receptors are orange these are all of the inhibitory |
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| 10:51 | And most of the synopsis as you see have formed on the democrats in |
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| 10:54 | the settlements. So if you have organization and abnormal organization of the Madrid |
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| 11:01 | the lack of it. And do expands. You will not be able |
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| 11:04 | process information properly and the cell has process information from hundreds thousands sometimes tens |
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| 11:13 | thousands of synopsis that are excitatory will the cell get more excited and communicate |
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| 11:19 | information to another salad on the And inhibitory cells. It will inhibit |
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| 11:24 | sell sell sell stay down, be , don't talk to the other connected |
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| 11:31 | and not for some no you have jump through a couple of slides and |
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| 11:39 | here mm. Most neurons as we how for functional regions so you can |
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| 11:45 | them. You have an input region region. The Selma conduct. I'll |
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| 11:50 | which is your axons and the output which is a sign ups. And |
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| 11:55 | output can be on another neuron and muscle on the small capital in the |
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| 12:02 | . Or even on neuroendocrine system, releasing hormone systems as well. We |
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| 12:08 | classify neurons as you as you recall on their anatomy and based on the |
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| 12:16 | and what that means is that Unipol typical invertebrates cell has only one |
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| 12:22 | It's only one north pole bipolar cells will study when we study the retinal |
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| 12:29 | have two poles. They have a pole and the house south pole pseudo |
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| 12:34 | polar has two poles but it has axons so it has a peripheral accent |
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| 12:40 | the central accent. An example of unit polar cell is the dorsal root |
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| 12:46 | cell. It's a sensor in Iran that projects information from the periphery with |
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| 12:54 | acts on picks up that information takes to the selma and from their projects |
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| 12:59 | the spinal cord. And then most the neurons in the brain are multipolar |
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| 13:05 | as motor neurons. Multipolar. You uh parameter excited to the south of |
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| 13:11 | motor polar. We'll talk about And one of my favorite south anatomically |
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| 13:17 | Kinji sellers cerebellum That contains up to synopsis on this massive and really |
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| 13:28 | The other way that we classify in answers. Some of them do not |
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| 13:32 | the great expanse and all the spine that's normal way to look at the |
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| 13:36 | to uh some of the neurons are to production cells and they will release |
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| 13:44 | excited during neurotransmitter glutamate and other And what that means the production |
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| 13:50 | That means that that cell excited resell project out and communicate the information from |
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| 13:56 | sell this axe on is going to long and is going through on to |
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| 13:59 | part of the brain or another part this anatomical structure. The into neurons |
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| 14:07 | short axons and they will control activity a local network level, controlling the |
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| 14:14 | cells on what the projection cells communicate to the interconnected networks. Excitability, |
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| 14:21 | to inhibitory south specific markers. Certain will produce their baptize their transmitters, |
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| 14:31 | binding proteins inside of them. And subtypes of cells will not finally action |
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| 14:38 | firing signatures, neurons produce these very fluctuations. About 100 million volts over |
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| 14:45 | milliseconds. Or so. The first potential recorded by Hodgkin and Huxley. |
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| 14:51 | the first published intracellular recording actually 1939 . Giant axon. So it's not |
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| 14:59 | giant squid that swallows the whole boat the ship but it's a giant axon |
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| 15:05 | in the squid that's about one And you can see it with your |
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| 15:10 | eye and established with a needle or with the naked eye as well. |
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| 15:16 | you have to think that in 1939 don't have computer controlled recordings, electrical |
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| 15:23 | . So this is a picture of silla scope and to capture that. |
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| 15:29 | use to have a freezing image on screen of the silla scope and then |
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| 15:34 | a Polaroid camera. Polaroid cameras came into style like some eight years ago |
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| 15:41 | when they went out of style again put the Polaroid camera and you basically |
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| 15:45 | an instant picture of that action And then how do you publish |
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| 15:54 | Quite interesting, right? Just the are very different. There's no |
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| 15:59 | there's no things like that. You , there's there there are called copy |
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| 16:04 | so you can copy things, you . So this is what you |
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| 16:08 | You basically at that time if you things you measure and you draw things |
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| 16:13 | you do in school. You know you do to do a geometry graph |
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| 16:17 | you draw something. So this is this is what the original paper submissions |
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| 16:22 | when we had, you know the of this modern neuroscience, if you |
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| 16:26 | back to some of the basic And of course when you send in |
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| 16:30 | of that original information and the that's another thing. Somebody would use |
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| 16:35 | paper, they send you red mark coffee, Somebody reviews your paper in |
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| 16:44 | . And guess what you have to . You have to re type the |
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| 16:49 | thing on the typing machine on the . All right. So there is |
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| 16:56 | . So you don't do it. don't mess up, you don't mess |
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| 16:59 | . There's no spell checker on a ? The grammar shaka. Nothing. |
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| 17:05 | , so this is this is just to give you an idea of what |
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| 17:08 | guys recorded this action potential. I mean, I don't know what |
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| 17:14 | your Giovanni didn't know. But Ramon didn't know. We now see that |
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| 17:19 | cells not only produce electrical activity and contract The muscles or the muscles contracted |
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| 17:28 | , but the record, we now record action potentials in 1939. And |
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| 17:35 | World War two actually, there was lot of technological development of the special |
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| 17:39 | the Navy side and a lot of electronics and electrophysiology equipment was adopted for |
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| 17:47 | research from Navy as well. For , in the lab we use |
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| 17:54 | cables, electrophysiology equipment that's called N. C. And you'll have |
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| 17:59 | same BNC cables and all of the and us harmony. So this things |
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| 18:06 | detection of silla scope seminars and things that, that the overlapping with modern |
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| 18:13 | and allowed than after World War Two do more precise recordings. And then |
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| 18:18 | around uh nineties uh 2000s it became that the brain contains over 150 or |
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| 18:29 | different subtypes of neurons. And so will be a very important question |
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| 18:35 | it was first, what does this do? Is it important or is |
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| 18:38 | hard important Then when you figure out inside the brain, all these |
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| 18:43 | ventricles must be important. And you out, oh there's electricity, |
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| 18:49 | We haven't talked about it but we know that there's synaptic transmission. Chemical |
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| 18:53 | transmission. So you build all all that information. You want to localize |
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| 18:59 | function that broke us area. That's area. That's crude anatomical description of |
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| 19:07 | area. What is subtypes of the and Broca's area? So at the |
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| 19:12 | of the 20th century, beginning of century now, modern neuroscience is getting |
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| 19:17 | understanding precisely how, oh my I didn't start recording. Oh |
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| 19:26 | So I don't want to repeat all that. So now the question |
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| 19:33 | what are these different sometimes? How we distinguish them? We just talked |
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| 19:38 | the specification. Is it just all ? Is it all the cellular |
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| 19:42 | What is more in there? And let's go over the anatomy before we |
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| 19:47 | about the function. And there's aspects anatomy that we discussed here. So |
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| 19:51 | said that this is hippocampus, one the most studied structures in the |
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| 19:57 | It has three dominant players already autumn the dollar and orients. And if |
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| 20:03 | look at the circuit, it has 21 different subtypes of cells and these |
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| 20:12 | that are in green, blue and here are excited to our criminal |
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| 20:16 | Most of excited for criminal cells are indian positive or cbP plus and they're |
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| 20:22 | in this pyramidal a layer right on of each other, right next to |
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| 20:26 | other in very high density. That's it's called. Perimeter layer. There's |
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| 20:31 | other excited ourselves that our orients and adam. And the point is that |
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| 20:37 | parameter excited to ourselves which are multipolar are projection neurons. Which means that |
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| 20:43 | information from this network from this entire which is called C A three from |
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| 20:50 | network is going to be communicated to network solely through the projection cells. |
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| 20:57 | there's going to be a lot of , a lot of analysis, a |
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| 21:01 | of local activity in the circuit going . But that activity is local activity |
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| 21:07 | these local circuits and the projection cells communicate that activity into the interconnected areas |
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| 21:15 | hippocampus or toronto cortex cortex that is close to the hippocampus. So how |
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| 21:23 | we distinguish between these 21 different subtypes cells and anatomical and morphological e. |
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| 21:30 | a lot of things that we can to distinguish them. It depends where |
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| 21:34 | so much are located. So there a few inhibitor into neurons that have |
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| 21:38 | much in the through the dollar But most of them are either in |
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| 21:44 | Autumn or orients. And some of inhibitory cells will have these vertical gun |
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| 21:49 | and others will have horizontally projecting These are all queues. These are |
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| 21:54 | anatomical morphological cues that you're working with subtypes of cells and you say like |
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| 22:00 | do you want to know that? uh As I said, the challenge |
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| 22:05 | the 21st century is to ultimately know every synapse is doing in every south |
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| 22:11 | do sell non invasively while still tracking gross activity in the whole brain. |
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| 22:18 | to get to that level, we to understand what these individual cells are |
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| 22:22 | , what their functions are, how are all different and how they influence |
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| 22:26 | activity that projects out of these Then when you look at some of |
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| 22:32 | , we said that they look quite . So number two, number 4 |
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| 22:36 | are located and pyramidal in then drives projecting vertical. These synapses which are |
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| 22:43 | cups. There's another way that you between into neurons. Some of these |
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| 22:48 | cups and into neurons will connect onto optical them rights. And other yellow |
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| 22:54 | will target the paras, somatic and regions of the parameter cells. But |
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| 23:00 | you look at two and four there's there. Yellow cops targets the same |
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| 23:06 | . So what is the difference between and four? They look the |
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| 23:09 | They're located the same. The synaptic or connectivity on the phenomenal South is |
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| 23:15 | same. You then look at one cells. These are called basket cells |
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| 23:20 | providing them positive and it's a calcium protein. That means it's genetically expresses |
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| 23:25 | calcium binding protein. And to provide and sell, sorry in the Basket |
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| 23:30 | , that's number four does not have them. Instead, it has another |
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| 23:35 | which is called CCK or solar system . So ultimately the difference between these |
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| 23:41 | cells is the specific marker cellular The distinguishes number two basque itself. |
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| 23:50 | four baskets. However, if you want to do this work and submitted |
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| 24:00 | the journalist that will accept this work accept this work in your telling the |
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| 24:06 | that I'm recording from parameters how and recording from pick a number number 14 |
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| 24:13 | . All right. Was number Okay, let's say # seven. |
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| 24:19 | gonna do an experiment on number seven is all the lamps sell one of |
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| 24:24 | favorite south and parameters south. And have About five professors around the |
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| 24:31 | Get my paper and I have to them That I recorded this activity that |
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| 24:39 | recorded phenomenon would have a seizure activity I'm studying in vitro. I have |
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| 24:44 | convince them that I did record from seven and not from number 15 and |
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| 24:50 | from number 16 And now from number . Why? Because seven. And |
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| 24:55 | other numbers I'm talking about 15, , 17. They kind of look |
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| 25:01 | . So how do you do this of work? You do this kind |
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| 25:04 | work And in vitro and slice You have a slice of the brain |
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| 25:11 | pressure prepared is preserved. And it's life. And you do electrophysiology. |
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| 25:16 | recordings. So in addition to the and south pacific markets which you don't |
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| 25:22 | when you're starting to experiment unless you some sort of a transgenic animal which |
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| 25:29 | be done these days, you can have a transgenic animal that will have |
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| 25:33 | of these subtypes of cells glowing with and you can target it. We're |
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| 25:39 | about animal research and transgenic MILES models particular. But if you don't know |
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| 25:46 | you have a normal tissue that hasn't genetically altered, that doesn't have a |
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| 25:50 | , this is expressing fluorescent inside the . What do you do? You |
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| 25:55 | it under the microscope? You visualize using infrared differential contrast that we discussed |
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| 26:02 | the infrared cameras. And then you these electrodes and these electrodes pass electrical |
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| 26:11 | into these cells. And what you do now is you can pass the |
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| 26:15 | same stimulus, the exact same electrical of these two cells, essentially, |
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| 26:21 | two cells are getting the same Now the cell on the left response |
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| 26:28 | the very fast each one of these going up and down vertical lines represent |
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| 26:37 | individual action potential and the cell on left responds by firing a very fast |
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| 26:45 | of action potentials is quiet high The cell on the right, it |
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| 26:52 | the same identical stimulus. The cell the right produces a very different pattern |
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| 27:00 | action potentials. So this is your ongoing experiments. You, too. |
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| 27:05 | see two cells there next to each . They look morphological lee different but |
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| 27:10 | don't see through infrared. Ir the anatomy, you see the selma's, |
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| 27:16 | stimulate them with the same stimulus. respond differently. That's a good |
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| 27:21 | You're onto something. Okay. during the experiment there is another guy |
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| 27:27 | we haven't discussed that you can place the electrodes. It's called neuro biotin |
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| 27:32 | bias tighten. And during this electrical during this experiment that die will |
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| 27:39 | will infuse inside the neurons and it diffuse throughout all of the processes of |
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| 27:49 | minerals. So now you did a of experiments, you recorded some electrical |
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| 27:54 | in two cells. Maybe you manipulated , Maybe you apply some chemical. |
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| 28:00 | you want to confirm post talk after experiments finish that you really recorded from |
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| 28:06 | seven South, like I was telling . And the criminal South. So |
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| 28:11 | is a neuro biden die and you develop that die and reproduce the precise |
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| 28:16 | of the cells and they will look similar. Another die that we saw |
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| 28:21 | desert is a golgi stain. Golgi reveals precise anatomy of all of the |
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| 28:27 | . And you can very clearly see is the selma and then black. |
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| 28:31 | see that done rights coming off horizontally then you have this Axiron that goes |
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| 28:37 | the optical regions here and then you this parameter sound Gramajo cell has its |
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| 28:44 | them dries and has an accident. accident is actually coming at you. |
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| 28:48 | going out of the plane that's a acts on going into an adjacent region |
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| 28:53 | the hippocampus. But that is still enough. I still don't know whether |
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| 28:59 | cell Is # seven or maybe number . I don't know. I still |
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| 29:07 | know Or maybe number 17. So in order to get your work in |
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| 29:15 | really good journal, you have to a double a triple immuno histology. |
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| 29:20 | in you know, it's the chemistry which you use antibodies that are directed |
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| 29:25 | specific cell markers. And I showed this cell that I was recording from |
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| 29:32 | talked like a number seven cell that like a number seven cell in fact |
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| 29:38 | semantics happened and it's a mark of marker that confirms that his numbers haven't |
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| 29:45 | . And it also is positive for , which is minor abidance. It's |
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| 29:49 | salary recorded from. It's very tough do these kinds of experiments. You |
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| 29:55 | simultaneously record from several cells at the time. But this is the only |
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| 30:00 | that we're getting to what single cells do and what individual different subtypes of |
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| 30:08 | , how they behave and how they the activity of the projection selves. |
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| 30:14 | so in in in reality when you at the circuit and you think about |
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| 30:19 | of the things that I was telling like brain waves oscillations up and down |
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| 30:25 | . Brain waves are also brain maps they travel through brain tissue and we |
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| 30:29 | activity maps. And the complexity of activity. And the complexity of the |
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| 30:36 | waves comes from the diversity and the of the inhibitory results. Think about |
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| 30:44 | excited ourselves. They have to reliably an action potential and excited distal |
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| 30:51 | These 21 different sometimes themselves. They to do a lot of control of |
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| 30:56 | of these projection neurons. And guess ? If you look at another patch |
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| 31:01 | the grains such as neocortex, what would see as you would see an |
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| 31:08 | and the collection of different neurons. if you were to place an electra |
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| 31:14 | is a small patch of cortex just couple of centimeters uh and in |
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| 31:22 | And you will record from many different in this cortex which you will find |
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| 31:28 | that all of these different solid different dialogues. So the same language |
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| 31:36 | an action potential. But it's a dialect and you can stimulate these cells |
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| 31:42 | exactly the same stimulus and they will very differently. And so I like |
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| 31:47 | do this invitation here. We actually these kind of recordings where we transform |
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| 31:56 | into an audio sound and the I'll just do it for you. |
|
| 32:01 | this cell gets stimulated and you can the cell doesn't produce action potentials right |
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| 32:06 | but it's delayed. So if I to imitate the cell vocally would be |
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| 32:12 | this stimulus song. Mm That's the of the self speaks right next to |
|
| 32:25 | . There's another cell is also So stimulus sang. But when it |
|
| 32:32 | on it will just produce a continuous . What we call the continuous frequency |
|
| 32:38 | these actual potentials. This is a sell and at first it produces a |
|
| 32:45 | and then it goes into fast frequency and then it slows down over |
|
| 32:52 | So this would be stimulus song. is a regular bursting cell. Which |
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| 33:05 | that despite the fact that is receiving exact same stimulus as these guys here |
|
| 33:09 | top. But instead of having this changing number and potential it produces these |
|
| 33:16 | up and down and on top of oscillation it has a train of action |
|
| 33:21 | writing. So it sounds like this song. This one is continuous stimulus |
|
| 33:39 | . This is the code. It's a morse code. Now you have |
|
| 33:49 | very complex morse code that is encoded different subtypes of neurons where each one |
|
| 33:57 | these neurons depending on the slightly different genetic expression proteins, channels ionic |
|
| 34:06 | Things like that produces its own dialect is speaking And these inhibitory cells and |
|
| 34:12 | subtypes of inhibitory sauce that I was to your Hippocampus. They will all |
|
| 34:16 | their own dialects of speaking to the sounds and out of this. Out |
|
| 34:22 | this it's like instruments right? Think the symphony. You come in the |
|
| 34:28 | and before the concert starts it can your ears. The fluid is blowing |
|
| 34:35 | loud and the violin is trying to in south and it sounds like a |
|
| 34:41 | . Every instrument is doing their tuning their own and then it goes |
|
| 34:48 | and then it starts out first Second vinyl tympani in the back starts |
|
| 34:54 | and oh and all the violence together woodwind instruments and so on. And |
|
| 35:00 | all coherent and it could break down chaos again and become coherent again. |
|
| 35:06 | so this is how it is from individual activity of these cells comes across |
|
| 35:12 | and activity in the network. That an oscillation, that activity in the |
|
| 35:17 | and gets communicated to the adjacent and brain regions. And these patterns are |
|
| 35:27 | different thoughts, different emotions, different in which we encode motor patterns of |
|
| 35:34 | the output that we have comes from different instruments or self contributing to an |
|
| 35:41 | network activities. Yes. Oh, from A to Z. Um it's |
|
| 35:58 | interesting question whether this was adopted by military, from the military. I |
|
| 36:04 | that the military with the answer maybe that the military is very much interested |
|
| 36:09 | how this works so that they can it for different things. So there's |
|
| 36:15 | there's a division of military DARPA that's much involved in very progressive forward thinking |
|
| 36:24 | . They allocate some of the funds they think that um you see the |
|
| 36:31 | of the emergence of intelligence and the cortical microcircuits. So the interest that |
|
| 36:37 | intelligence, artificial intelligence is how to some of these circuits and obviously military |
|
| 36:45 | like to use it for uh destructive , not just for you know, |
|
| 36:52 | good things. So It's a good . I think everything is intertwined. |
|
| 36:57 | is just an example of what this would entail. I started telling |
|
| 37:01 | So you showed up in the lab at 8:30 pm you go to, |
|
| 37:07 | do you do? You go to fridge and a couple of rain slice |
|
| 37:10 | just record from it. No, can't, you have to go to |
|
| 37:14 | very um you have to get your or your rat most of these |
|
| 37:18 | abdominal mouse or rat brain slices and have to anesthetize animals. Do the |
|
| 37:25 | protocol, prepare your solutions, prepare place to slice and artificial service spinal |
|
| 37:31 | . That's exaggerated. So that the things is still a part of the |
|
| 37:35 | because guess what? You know, need oxygen and so you need to |
|
| 37:40 | them with cerebrospinal fluid equivalent and oxygen oxygen comes from the lounges and the |
|
| 37:47 | goes into your neurons and neurons as I mentioned, a very needy |
|
| 37:51 | oxygen, very sensitive. And so this case it takes about an hour |
|
| 37:57 | a half to have a slice brain sitting underneath this, let's hear, |
|
| 38:04 | , the microscope. And then uh have a whole computer equipment to silla |
|
| 38:11 | , amplifiers connected to it have a of about maybe a quarter of an |
|
| 38:19 | here. Something to work with When trying to place four electrodes in there |
|
| 38:24 | before you know, it's like six Whoa, you know, the slices |
|
| 38:30 | alive about 10, 12 hours. you kind of do this experiment |
|
| 38:35 | but you also kind of just do for an hour. I'm done. |
|
| 38:39 | know, another right tomorrow, who ? You know, you kind of |
|
| 38:44 | , you have to be dedicated to and then six popular regardless and stuff |
|
| 38:48 | . And then instead of using sophisticated , you put a pen holder here |
|
| 38:54 | a, from a pen, you see to hold your little pre amplifier |
|
| 38:58 | , you get that magical experiment before of eight p.m. The following day. |
|
| 39:04 | can show up at 11 documentaries, one o'clock, you should see what |
|
| 39:12 | had and I'm like, okay, can do what you do keep doing |
|
| 39:19 | you do. So it's, it's tough to do these experiments and, |
|
| 39:24 | in my life I have done what call the multiple patches, multiple sell |
|
| 39:31 | at the same time. And my interest wasn't understanding what different subtypes of |
|
| 39:37 | are doing in starting a seizure So I wanted to know, is |
|
| 39:42 | excited to yourselves that starts seizure, inhibitor assaults, which ones are active |
|
| 39:49 | . And it turns out it's an songs that become active first and then |
|
| 39:52 | failed, which allows for excited to to synchronize and produce abnormal activity, |
|
| 39:59 | spreads throughout the brain tissue. But was experimentally never shown before on a |
|
| 40:05 | level in in in this way. it's very exciting. And then you |
|
| 40:09 | , okay, what does it have do with the human brain and human |
|
| 40:16 | ? Just like uh studying fruit fly , zebrafish your system. So you |
|
| 40:25 | easily studying, you can have a end, They reproduce easily. You |
|
| 40:30 | need animal protocols or flies for Um you take it a step further |
|
| 40:40 | the dish. You want to prove in a whole animal. And quite |
|
| 40:45 | what you see in the dish. will then start reporting seeing in the |
|
| 40:49 | as well. And it is usually way that some crazy scientists are sitting |
|
| 40:56 | stabbing hundreds of cells in the middle the night. And then some |
|
| 41:02 | neurologists that are very interested in your are reading it are in the |
|
| 41:07 | They go back and look at the recordings, brain activity and like |
|
| 41:11 | we see similar stuff there too. know, so there's a real dialogue |
|
| 41:16 | enrichment, the two way enrichment between and basic science that happens here. |
|
| 41:24 | , so we're a long winded today we will start talking about glia, |
|
| 41:32 | just neurons and for a while glial thought to be just support installation functions |
|
| 41:38 | rather passive, just like the dough the cookie. But we know that's |
|
| 41:43 | the case. Micro glia for the scavengers, they are responsible for |
|
| 41:48 | repair and cleanup in the brain if is a damage and micro clear, |
|
| 41:54 | only that they're also involved in pro side of kind. So they're involved |
|
| 42:00 | the inflammatory processes and regulation of the processes in the brain. So, |
|
| 42:05 | you go into your folder, Um and uh in the blackboard, |
|
| 42:14 | not it. This was bad. . So I'm trying to or fix |
|
| 42:27 | for a second. Yeah, This uh what is happening is a time |
|
| 42:40 | . This is 10 micrometers in distance time lapse. So we'll see the |
|
| 42:44 | . But it's uh minutes, two . And what happens here in the |
|
| 42:51 | where you have this bright yellow ball where the site of injury takes |
|
| 42:56 | And you can read the details if want in the description in the |
|
| 43:01 | But suffice to say this is where injury happens. And these cells that |
|
| 43:06 | standard micro glial south stand with a stanford microglia. And what they show |
|
| 43:12 | that immediately after the injury. Microgreens growing their processes and extending their processes |
|
| 43:19 | . The site of the injury. then over time they actually even start |
|
| 43:27 | into the area moving there so you can see the soul must move |
|
| 43:31 | there over here closer into the location the injury. So Michael Glia is |
|
| 43:38 | responsible for damage repair but also control inflammation in the brain. And Michael |
|
| 43:45 | are the most dynamic units in the . Because they can actually move through |
|
| 43:51 | brain tissue. So as the injury in a specific part of the |
|
| 43:58 | they get recruited, so to by the signals and by the inflammation |
|
| 44:03 | injury that happened there. They get the control inflammatory processes. But they |
|
| 44:10 | Russian physically to take care of the the damage. So that's Michael |
|
| 44:19 | I'd like to please move down The next cells that we will discuss |
|
| 44:33 | Well I'm sorry I had a question I and I and I missed the |
|
| 44:37 | . Yes. So I think we're can use social and energy. What |
|
| 44:44 | you mean? Unlike they're all cells unlike other glial cells. Uh They're |
|
| 44:57 | very much so types of them in . But they're also part of the |
|
| 45:02 | grill networks. So they are involved the immune response. They're involved in |
|
| 45:06 | pro inflammatory cytokine release. Uh They in the brain and I don't know |
|
| 45:15 | you can call them exactly just immune . Uh huh. Stop waiting. |
|
| 45:22 | you. Or creative. Are you me are you telling me because |
|
| 45:36 | Yes. They're grouped together with real . Yes. Yes. It's a |
|
| 45:40 | a it's a good question because the of these cells. And I don't |
|
| 45:44 | I'm having such a hard time with this window down of mm hold on |
|
| 45:53 | say and I have to stop the you know for some reason just Oh |
|
| 46:06 | . Yeah. Mm. Yeah. . Mhm. It's not it's glial |
|
| 46:27 | so like I said I'm not responsible uh some of the commercials that come |
|
| 46:32 | front of some of these uh movies her. Uh Now let me open |
|
| 46:47 | why am I? Yeah. Mhm. Yeah. Yeah. Uh |
|
| 47:06 | . Oh I'm recording this whole Great. Okay so now we're the |
|
| 47:13 | type of cell that we're going to this radio grill. So and radio |
|
| 47:17 | cells are involved in guiding neuronal migration process outgrowth. And they can also |
|
| 47:25 | as neuronal and glial precursor cells. you're a potent precursor cells, what's |
|
| 47:31 | about neurons is that neurons are not in their final destinations. How you |
|
| 47:36 | them all scattered in the cortex, actually have to reach that final |
|
| 47:41 | They're forming a special parts of the and from there they migrate and find |
|
| 47:46 | final address and the layer in a location in the brain and in order |
|
| 47:52 | facilitate this migration you have radio glial and those radio glial cells uh as |
|
| 47:59 | see in this video serve as a neurons will form cytoplasmic continuity with the |
|
| 48:08 | glial cells and use it as a to help climb to help migrate and |
|
| 48:15 | its final destination and its precise location then there is a another uh huh |
|
| 48:31 | . I think I may have opened . Commercial hopefully doesn't commercially on the |
|
| 48:38 | so you can see that it's a migration that's happening and uh there's neurons |
|
| 48:48 | with each other and neurons are using glial cells to advance themselves into their |
|
| 48:53 | destinations in the brain. The third of leah is an ostracized and astrocytes |
|
| 49:09 | here as housekeeping tourists, neurotransmitter and uptake. And believe me housekeeping chores |
|
| 49:15 | very important. It's like flushing the . What happens is fairly different. |
|
| 49:19 | flushed uh and it's not just housekeeping . These are actively influencing neurotransmitter levels |
|
| 49:28 | the synapses. Influencing ionic concentrations around and around synopsis and actively controlling |
|
| 49:38 | The genesis of formation of the synopsis influencing synapse number synapse function and the |
|
| 49:46 | strength or a level of plasticity that are responsible for ostracized also form a |
|
| 49:55 | of blood brain barrier as well. this is there other functions that they're |
|
| 50:01 | in blood brain barrier formation. But and like neurons do not produce action |
|
| 50:08 | . Instead they produced these very slow authorizations that are mediated by calcium And |
|
| 50:16 | a way you can start thinking that are this multiple different Temporal processing scales |
|
| 50:24 | the brain. There are some neurons can fire 600 Action potentials for |
|
| 50:31 | Hz. The neurons that fired three potentials per second. Three hertz. |
|
| 50:38 | they're glial cells that produce these very seconds long deep polarization is that spread |
|
| 50:44 | calcium throughout the interconnected network. So much slower level of activity, much |
|
| 50:54 | level of managing the fasten attic transmission is happening at the same time in |
|
| 51:03 | . Glial cells are responsible for mile in the periphery. It is a |
|
| 51:09 | cells that will each individual Schwann cell form an individual segment of myelin on |
|
| 51:16 | peripheral nerves. Embassy and S. illegal dangerous sides that have multiple |
|
| 51:23 | And each one of these processes will responsible for wrapping around and forming an |
|
| 51:29 | segment of mild in between these smile segments. There is a break and |
|
| 51:36 | referred to as Note of Ranveer. note of ranveer contains quite a bit |
|
| 51:40 | a. T. P. As as high density of sodium and potassium |
|
| 51:45 | that are necessary to regenerate the action . They would get formed relax an |
|
| 51:51 | segment. So ostracized still most of space in the brain that is not |
|
| 51:59 | by neurons and blood vessels. So are quite more prevalent. But illegal |
|
| 52:05 | sides are the ones that are responsible formation of mile and and wrapping off |
|
| 52:10 | mile and sheet around the axons in cns. Mhm. So let's talk |
|
| 52:21 | little bit about myelin dysfunctions and how process happened. There's a slew of |
|
| 52:28 | , the number of proteins that control Myelin Nation and Myelin confection process. |
|
| 52:35 | have about seven related proteins, So Myelin associated glycoprotein mod, which |
|
| 52:42 | responsible for initiation of the island but also for things like South cell |
|
| 52:49 | . All right, so you have cell trying to touch another cell. |
|
| 52:53 | have to recognize another cell. And accent of that cell has to recognize |
|
| 52:59 | proteins and say, okay, we're wrap around me. This has to |
|
| 53:05 | , Right. And so it's complex . And if you have abnormal uh |
|
| 53:15 | protein level, sort of normal expression these different related proteins, you can |
|
| 53:22 | a dim illumination in the central nervous . When we talk about dim |
|
| 53:29 | we talk about another disease, It multiples for the roses. Multiple sclerosis |
|
| 53:36 | an auto immune disorder, which means its own immune system starts recognizing Myelin |
|
| 53:46 | elements in the myelin as foreign invader starts essentially destroying its own violent |
|
| 53:54 | Its own dim illumination is auto auto induced happens because of the chromosome |
|
| 54:02 | T mutation is not the only mutation can lead to multiple sclerosis. But |
|
| 54:09 | in this particular model of multiple And in general the symptoms of multiple |
|
| 54:16 | would be tremors and convulsions. So would be some of the motor symptoms |
|
| 54:21 | you may have traumas. Convulsions, . Because you have the Myelin Nation |
|
| 54:27 | central neurons. The central neurons are controlling the activity of the spinal nerves |
|
| 54:34 | well and therefore not controlling the border . So you will have the spasms |
|
| 54:38 | the muscles and cramps and uh you the imagination and the C. |
|
| 54:44 | S. You'll have all sorts of that are affecting uh neurons not just |
|
| 54:52 | and convulsions. And in order for master form you have to have two |
|
| 55:00 | out wheels. It's a recessive, form of genetic disease and the onset |
|
| 55:09 | multiple sclerosis. So Alzheimer's onset was asian population, fragile acts was developmental |
|
| 55:17 | . Uh multiple sclerosis onset is typically from 30s onward. Now, if |
|
| 55:25 | do an experiment, you have a with a genetic mutation chromosome maintain you |
|
| 55:31 | to battle eels you produce a shiver . The sugar mouse essentially will be |
|
| 55:38 | a human symptomology of tremors and Uh And this is a normal mylan |
|
| 55:47 | you can see a lot of mill stand in black that's wrapped around the |
|
| 55:53 | . This you can see the mill is very scant. It's very just |
|
| 55:59 | few layers and some of them are at all. Sugar mutants. Then |
|
| 56:05 | can transfer act normal gene back into animals. So this is an example |
|
| 56:12 | gene transfer action where you inject the and you hope that that gene generates |
|
| 56:16 | myelin maybe fixing the amount of protein allowing for that cell phone recognition to |
|
| 56:24 | place. And so you can restore the modern nation in this land. |
|
| 56:29 | you can you can do these And again, without animal experiments, |
|
| 56:34 | wouldn't know a lot of information about is happening in humans in the |
|
| 56:41 | You have a different problem in the . There is a protein that's called |
|
| 56:46 | . m. p. 22. . m. p 22. Uh |
|
| 56:52 | gene duplication chromosome 17. An overproduction p. m. 22. There |
|
| 56:59 | a development of what is called Charcot to disease. And you can see |
|
| 57:04 | this is a normal oxen in the . And this is struck out Marie |
|
| 57:09 | disease. You can see that there's lack of that stain. There's a |
|
| 57:12 | of my island nation. And you pick up actually uh in staying for |
|
| 57:18 | gene duplication. And you can stay for PMP 22 as well Now. |
|
| 57:24 | multiple sclerosis, which we said the is typical in the 30s, Charcot |
|
| 57:29 | Tooth is also developmental disorder. So is no cure for sharp out merited |
|
| 57:36 | and because of the abnormal stimulation of muscles, especially in the legs and |
|
| 57:43 | extremities, abnormal stimulation of muscles will cause deformities in the bones and the |
|
| 57:50 | in the bones can then cause impact , abnormal kind of a swinging like |
|
| 57:57 | and other bodily deformities that just follow lower extremities into the upper body |
|
| 58:03 | So the only way to combat shark narrative diseases, really to have as |
|
| 58:09 | diagnosis as possible and then use braces ankles and knees and certainly hip |
|
| 58:17 | source of racist to preserve as much possible of a normal bone structure. |
|
| 58:23 | it would help individual to control their their motor functions. They're walking forward |
|
| 58:31 | in particular a lot of times uh Marie tooth disease patients will have the |
|
| 58:38 | walk from side to side instead of forward walk because of the deformities of |
|
| 58:44 | lies that would have more of a step, kind of like swaying |
|
| 58:50 | And this slide puts almost everything in . In particular all of the cells |
|
| 58:58 | we discussed. The legal tender sighs for my island nation micro glial cells |
|
| 59:05 | for um damage repair information control involved the immune response in the brain astra |
|
| 59:14 | that are very intricately controlling synoptic synaptic activity, neurotransmitters and ions and |
|
| 59:23 | the and feet of the extra sized of blood brain barrier. You also |
|
| 59:28 | the tandem all south dependable South of the space between the cells that contain |
|
| 59:35 | fluid, interstitial space and there is that contain large amounts of cerebrospinal |
|
| 59:43 | You have a pendulum ourselves that provide that barrier between the actual cell environment |
|
| 59:49 | the Subaru spinal fluid that is in ventricles. There's defendable cells interesting |
|
| 59:55 | They're emerging sort of a potent sauce could become either neurons or glia |
|
| 60:03 | And the last subtype of real cells we didn't show here is radio Real |
|
| 60:08 | . We refer to that are involved early neuronal migration during the early development |
|
| 60:16 | brain barrier. We talked about it very first lecture. This is the |
|
| 60:21 | last slide. Maybe we'll go and your movie Or a quick one |
|
| 60:29 | But you have and the theory of here and they are essentially your blood |
|
| 60:35 | walls and they are containing tie junctions . That means things kind of pass |
|
| 60:42 | tight junctions unless they're supposed to pass they're really small or unless they have |
|
| 60:48 | that bring them across the cellular You have parasites surrounding the ethereal functions |
|
| 60:55 | the surrenders blood. And finally you the astra glial processes that surround the |
|
| 61:03 | and the basement membrane here and so all of these elements, the high |
|
| 61:11 | and you're agree or a specific and . You have a tight control of |
|
| 61:17 | is in the blood to what gets the brain. You don't want things |
|
| 61:21 | go into the blood to get into immediately into the brain, certain things |
|
| 61:24 | want to get into the brain. things you do not. So let's |
|
| 61:30 | if I can yesterday. I just . And they yeah. A search |
|
| 61:40 | it said something like Cymbalta. It's depression medication. And I'm not advertising |
|
| 61:52 | right, Cymbalta or anything like I don't know if it's a commercial |
|
| 62:01 | not. But when I looked up actually I looked up for anxiety medication |
|
| 62:12 | . Yeah Cymbalta showed up was the one. U. S. |
|
| 62:15 | O. Not affiliated with Cymbalta. don't promote Cymbalta. I don't use |
|
| 62:27 | . It's the first thing I talked him. I do that for a |
|
| 62:31 | because it's interesting too important to think the world and the brain a |
|
| 63:31 | So you're treating a neurological when a psychiatric disorders, depression, anxiety, |
|
| 63:40 | and you're having severe liver problems. is that all the drugs that are |
|
| 63:49 | is probably the secondary metabolism that happens liver. And so a lot of |
|
| 63:54 | substances you put in and the drugs you put in the medications they get |
|
| 64:01 | processed by certain enzymes and cider chrome's the liver. Right? And that |
|
| 64:08 | that why you affecting the liver if treating the brain, that means that |
|
| 64:14 | medication you're using in order for it affect the brain, you have to |
|
| 64:18 | a lot of it and a lot it will have the side effect the |
|
| 64:23 | effects in this case peripheral side So liver yellowing of the skin, |
|
| 64:33 | pain. Again doctor about the medicines migraine or you have a condition, |
|
| 64:39 | to address a possible life threatening condition . And before you reduce for her |
|
| 64:49 | side effects nausea and constipation. We constipation. You hear a lot of |
|
| 64:56 | opiates uh for you use for pain depression opiates it will cause constipation And |
|
| 65:04 | a pharmaceutical drug that's opiate induced constipation . So you have drugs that are |
|
| 65:12 | only treating conditions but you have drugs are treating side effects created by drugs |
|
| 65:18 | conditions. Alright. Never first line defense is change your diet and go |
|
| 65:25 | this culture very fast prescription stuff very . Even for kids actually for |
|
| 65:32 | D. H. D. And like this. You know it's very |
|
| 65:35 | I think. Uh And the reason is because when you treat the condition |
|
| 65:41 | treating the entire body and most of medications, how did they get into |
|
| 65:46 | into the brain? How do you most of your medications for a |
|
| 65:51 | Exactly. So it's either that's the of delivering that medication in the |
|
| 65:57 | It is not because what happens when delivered early it goes and it gets |
|
| 66:03 | by gastric juices, ph four ph some of the things get destroyed. |
|
| 66:10 | to pass bypass gas reduces get into intestinal environment. That's where you have |
|
| 66:16 | of that. Some of the things happen. Sublingual E. And |
|
| 66:22 | There's some drugs that you can dissolve the tongue and that's very good absorption |
|
| 66:27 | that bypasses the whole intestine or pathway digestive pathway, right? But most |
|
| 66:36 | the things you swallow with water, of the things you don't chew and |
|
| 66:40 | around your mouth on your cheeks are your tongue where you have most of |
|
| 66:44 | absorption here in the upper is a environment so you swallow stuff by the |
|
| 66:51 | is swollen enough stuff that it gets the digestive system and to the blood |
|
| 66:58 | passes through the blood brain barrier and or fact on yourselves. Okay, |
|
| 67:04 | what you want to do when you're about neuro drugs, you want to |
|
| 67:10 | drugs that are very effectively getting into brain, how does the virus get |
|
| 67:17 | the brain? One of the ways the nose through the epithelium nerve |
|
| 67:25 | There is some spray medications through the spray, apple etc medications nasal sprays |
|
| 67:32 | get stuff in the brain. That's . Yeah. Another way is, |
|
| 67:38 | you get stuff through the skin? so you can get it locally. |
|
| 67:42 | can have a local concentration not coming your stomach, high concentration to treat |
|
| 67:47 | here here, but it's applied locally most traditionally, if you're still swallowing |
|
| 67:55 | and you want things that get absorbed into the body and that pass through |
|
| 68:02 | blood brain barrier effectively. So their brain barrier. Their lipid soluble drugs |
|
| 68:08 | pass through the liquid membranes and get the brain. So it's a great |
|
| 68:14 | . We have a blood brain barrier therapeutically and especially when we're talking about |
|
| 68:18 | development of neuro drugs, it's also significant challenge to overcome if you don't |
|
| 68:24 | to create a slew of side And potentially new medications to treat the |
|
| 68:28 | of Yeah. All right. So your weekend. This is a short |
|
| 68:33 | for you. I'll see you on next week. I'll see everyone on |
|
| 68:38 | next week on Tuesday. Take care question before just after class. But |
|
| 68:46 | was wondering if there are diseases that caused by having too much Myelin Nation |
|
| 68:51 | |
|
