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00:02 | this is Lecture four of neuroscience and ended up talking about how cells receive |
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00:09 | inputs and they received inhibitory inputs and neurotransmitters glutamate and the inhibitory neurotransmitters, |
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00:17 | , which is gamma immuno butyric They're both amino acid neurotransmitters and the |
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00:23 | 1000 neurons can receive hundreds thousands tens thousands of excitatory glutamate ergic inputs. |
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00:31 | , ergic synopsis glutamate will try to the south, will try to de |
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00:37 | them and make more positive charge inside south, telling the south to fire |
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00:42 | action potential to be active inhibitory Gaba binding to the inhibitory synapses in this |
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00:50 | will hyper polarized this neuron, adding negative charge into this neuron, telling |
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00:56 | neuron to stay the essence or silent to fire an action potential not to |
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01:03 | that information into this interconnected network. most of the synopsis is Ramona alcohol |
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01:12 | hypothesized early on form of dendrite dendritic and so Mazz and most of the |
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01:19 | synopsis earned. And dendritic spines and abnormal formation lost number densities positioning of |
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01:26 | spines can result in a more severe to where fragile lacks. It's actually |
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01:33 | genetic disease that ends up in severity that depends on the damage to the |
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01:39 | , which ends up damaging the protein is responsible for regulating other genes in |
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01:49 | these dendritic spines and see how different the two disorders are that we've discussed |
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01:58 | we then started talking about The fact in the 19th and 20th century we |
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02:09 | understanding what are different parts of the , how they look differently with the |
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02:14 | that we used were the scientists used we also realized that there are different |
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02:21 | of neurons and different subtypes of And so we started discussing how one |
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02:28 | sub classify or subtype these different the of neurons. And so we talked |
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02:35 | morphological descriptions, some salsa unit polar , pseudo unipolar. This is our |
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02:41 | root ganglion cells in the spinal cord cells in the retina that you learn |
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02:46 | . When we study the visual system neuron which is multipolar coming out of |
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02:51 | ventral side of the spinal cord is . The muscles have most of the |
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02:56 | in the cns and the cerebrum are . One of the most famed cells |
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03:01 | the excited projection parameter will sell because looks like a pyramid and it has |
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03:06 | apex and an ethical done drive. has the base and basal dendrite has |
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03:11 | axon that interconnects other regions of the . And you have this very Sophisticated |
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03:18 | . The cells of the cerebellum that have a 250,000 synapses. Therefore it's |
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03:24 | important to have precise anatomy and function the synopses of the downgrades and the |
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03:29 | expires so that these neurons can integrate process that information in a very fast |
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03:36 | and communicate that information. And once looked at classifying neurons based on the |
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03:45 | . We said there's also classification whether projection cells or whether local into |
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03:50 | And we said that projection cells like cells, they will project out of |
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03:55 | networks into the adjacent networks. They communicate, excited for information there. |
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04:00 | ergic cells. Most of the inter are local network cells and their inhibitory |
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04:07 | means they release Gaba, gaba ergic . So excitability, excitatory versus inhibitory |
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04:14 | specific markers which are very important. get back to that in the second |
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04:18 | neurotransmitters, neural peptides, the secular , receptor membrane proteins, trans membrane |
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04:27 | . They all can be slightly differently by these different subtypes of cells. |
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04:32 | we also need to know that information importantly, after we understand the location |
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04:39 | the cells, their morphology, what they express which is also their |
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04:45 | We also want to trace their electro properties which is the action potential, |
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04:51 | properties, passive number of properties which resting membrane potential and active member and |
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04:56 | of these neurons, which is these fast situations, 1 to 2 milliseconds |
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05:01 | duration of approximately 100 million volts in . So the first one was published |
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05:07 | 1939, but Hodgkin and Huxley. we talked about how difficult it would |
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05:16 | been to do these experiments and then more so how difficult it is to |
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05:22 | what you've done to people that were in the room and to convince them |
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05:27 | the absence of the modern technologies such um cell phones and computers. |
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05:35 | And we ended here with the last in this very important network. It's |
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05:42 | very important network because it is a well studied network. It's a it's |
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05:49 | popular structure in the brain. A of people know about it the |
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05:56 | if you're in psychology people talk a about hippocampus too. So if you |
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06:01 | psychiatry, if you and other memory sciences or if you're in the |
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06:07 | , computational neuroscience engineering, this is very good circuit to learn because there |
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06:16 | a lot of features of this circuit we call canonical features of this circuit |
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06:22 | the hippocampus. That means that this of arrangement is going to be likely |
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06:30 | in another part of the brain and circuit. There are certain rules by |
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06:34 | these neuronal circuits function. Hippocampus is part of the limbic system and the |
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06:40 | is responsible for memory formation, memory and also emotional memories and emotional processing |
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06:49 | general. It doesn't mean that memories stored in hippocampus in this one |
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06:55 | Memories are actually semantic memories in particular hippocampus is responsible for encoding are widely |
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07:02 | throughout the cortex. That's why if have the damage to one part of |
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07:06 | brain, you have a certain type damage but it doesn't mean like we |
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07:12 | about language areas. If you want take out somebody's language ability you have |
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07:16 | take many different parts of the brain them to completely lose that ability. |
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07:22 | now in hippocampus you have predominantly three stratum and stratum orients starting from the |
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07:32 | is Farrah middle cell layers stratum of layers. So it's a parameter layer |
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07:39 | 90% of these parameters all cells, of these phenomenal cell bodies. Selma's |
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07:46 | live in this lake. This structure a three layered structure and a lot |
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07:51 | times it's referred to as our key which is archaic cortex. It's archaic |
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07:58 | versus neocortex which is the cerebral neocortex a six layered structure. And hippocampus |
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08:05 | actually going through some sort of a evolutionary development and I think it's trying |
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08:12 | become neocortex also. It's trying to itself into potentially sick slave structure to |
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08:18 | that's what happens with activity with stimuli genetic uh Attrition and selection if you |
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08:26 | natural. Uh But so we have circuit and what are the teachers of |
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08:33 | circuit. You have these parameters ourselves this parameter cells look exactly the |
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08:39 | 90% live in the same layer. projection excited for ourselves. That means |
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08:45 | will project their axons outside of the into other parts of the brain. |
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08:52 | of the biggest projections from here goes interim final cortex. So these are |
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08:58 | ourselves. Some of them have their in audience and about 10% either than |
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09:06 | . If you were to stick an inside the cell it will produce the |
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09:11 | Exactly pattern of action potentials. If is still pending positive which is |
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09:16 | D. Plus or co dependent The only distinguishing factor here between these |
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09:22 | is an intracellular sell market and because have a slightly different expression the different |
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09:29 | cellular marker different intracellular molecule that they . Their physiology is different. They |
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09:36 | the second step time from excitatory Other than that they look the same |
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09:42 | they fire the same patterns of action all parameter cells in the hippocampus and |
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09:51 | job was to excite from this part the hippocampus. Other parts of the |
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09:58 | or other parts of the brain. boring but we're not boring. And |
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10:06 | happens is that we have a lot different complex sensors stimulate and coming at |
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10:11 | with different frequencies the light is coming hitting us with wavelengths 407 100 nanometers |
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10:18 | is coming and hitting our ear drums frequency 10 hertz to 40 kilohertz is |
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10:25 | audible human range tapping car vibrations. our sensors stimuli people shouting at |
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10:32 | somebody giving a good ideas, bad upsetting you. You know all of |
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10:39 | requires complexity. And if you just one and two subtypes of excitatory cells |
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10:45 | doesn't seem very complex. And this networking Hippocampus is three lead structures fairly |
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10:54 | but it's also fairly complex when the arises from the 21 subtypes of inhibitory |
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11:03 | . So these other cells in the . They all express and release |
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11:08 | Their inhibitory they release Gaba they're into which means that they will stick around |
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11:16 | the circuit and they will try to the activity of criminal cells in each |
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11:22 | . But ultimately they will sculpt and train the type of physiological activity. |
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11:30 | prom. It'll cells are going to able to communicate into the adjacent interconnected |
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11:36 | . So their role locally here is try to sculpt whatever pattern of activity |
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11:43 | the parameter cells are communicating or shut parameter cells because their inhibitory cells and |
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11:49 | them quiet. These inhibitors south are throughout the three layers. Someone that |
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11:57 | inhibited ourselves again, they live in same layer like two and four. |
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12:03 | have the same pattern here in These dead rights that are going |
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12:10 | These cops yellow cups are inhibitors And one of the things we want |
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12:17 | know is where are these inhibitors synapses on the promenade cells. Inhibition is |
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12:23 | lot more effective when it's targeting the and the accident initial segment because this |
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12:29 | the integrated region of the south. you can actually influence whether it's going |
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12:34 | find action potential or not. So and four has this inhibitor synopsis and |
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12:40 | all target the soma is here at pyramidal layer south. And the only |
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12:46 | again between the students themselves is that of them expresses the marker P. |
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12:52 | . Which stands for approval document and one expresses other markers which is |
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12:56 | C. K. And B. three. So you won't be responsible |
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13:00 | what type of sub type of cell two and four express which marker. |
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13:05 | the take home message is that these subtypes of cells even if they look |
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13:09 | same and have the same morphology the location and even the same number and |
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13:15 | properties that can still be distinguished by intracellular Uh cell markers that are unique |
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13:21 | makes them a different subtypes of This is from 2008. So it's |
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13:27 | likely if I look at the latest from the inhibitor subtypes of Hippocampal |
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13:34 | This number may be higher than 21 predict it's probably 26 or 27. |
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13:40 | at some point there was a discovery two or three different subtypes of different |
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13:45 | in Hippocampus and in the cortex almost a on a monthly basis. Uh |
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13:52 | you can see that some of these cells will target integrated regions. Some |
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13:58 | the synopses, inhibitory synapses will target of the south. Others will target |
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14:06 | output of themselves. But the most is that you can target the integration |
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14:12 | the cell makes up its mind. the cell makes up its mind and |
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14:16 | an action potential. You can maybe out outfit not as effectively though is |
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14:23 | the formation of that output. So is something I used to do for |
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14:29 | very long time. It's called patch wholesale electrophysiology uh also a lot of |
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14:38 | uh referred to as multiple wholesale recording multiple simultaneous real time patch clamping. |
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14:48 | uh I've done it for a long like I said um let's see if |
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14:59 | , okay. So what I did I explained to you that in the |
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15:03 | days you have to stay in the to visualize it. But then I |
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15:06 | we had these infrared cameras and microscopes you can put a slice of the |
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15:10 | underneath and you can actually visualize these . So I was recording in hippocampus |
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15:16 | I approach these neurons that attend microns diameter. I targeted these neurons with |
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15:23 | electrodes that are approximately one micrometer in diameter at the tip or less. |
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15:30 | are borosilicate glass electrodes. The electrode have inter cellular solution in them. |
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15:36 | inter cellular solution should be exact same very similar to what is inside the |
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15:43 | . So the electorate solution should be same as the inter cellular neuronal solution |
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15:50 | you essentially can poke these cells and can stimulate them. So assume that |
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15:55 | cell on the right looks like a cell. And I inserted the electrode |
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16:00 | the cell and I stimulated the cell I increased the stimulation. The second |
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16:06 | of stimulation. So I'm actually producing current in this electrode, pumping positive |
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16:12 | . I'm pretending a big excitatory input this electrode making the cell fire. |
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16:18 | I'm giving it a big input and what the output is going to |
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16:22 | And finally on this third stimulation and a few action potentials and then I |
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16:31 | the stimulus is stimulated even more, more positive current flowing in and the |
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16:38 | response now with this pattern of action and this is I know it's something |
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16:46 | parameter cells, this is the dialect parameters self speak, the action potential |
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16:51 | also patched the cell on the left I said you know what that cell |
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16:57 | the word was located and more than saw about it and all of the |
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17:02 | planes you're seeing a one focal I said I think that cell is |
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17:06 | interneuron and I had a hypothesis that cell is a particular type of |
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17:12 | this number seven which stands for O lam cells. Orients like and I |
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17:18 | like them because they had these horizontal rides. So we picked them out |
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17:24 | the slices and I inserted electorate in cell and I produced the same stimulus |
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17:31 | that left, sell the same amount stimulus has been normalized for other pe |
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17:36 | in the number right? As on right. And when I give it |
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17:41 | enough stimulus, this cell responded with fast frequency of action potentials that it |
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17:50 | it more stimulus firing it not really that frequency of firing. And so |
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18:00 | knew that that is not a phenomenal but I did a more of experimentation |
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18:06 | this. This is not a hunt self specific subtypes. This work was |
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18:11 | understand with different subtypes, neuronal subtypes doing during seizure like activity in |
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18:17 | My main question was which South starts in the brain or in the |
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18:25 | So the answer I found is that ourselves, start seizures, inhibitory cells |
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18:33 | to abnormal synchrony of excited to and inhibitory cells fail and allow for |
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18:38 | excitation to run away and propagate and to other parts of the brain. |
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18:44 | this was in vitro in a And, you know, people didn't |
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18:48 | that this kind of a pattern exists uh then people about 23 years |
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18:56 | I saw the same pattern in humans epileptic brains and inhibitory into neurons being |
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19:01 | active at the start of the So that's what you can sometimes |
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19:06 | it's like, what is this? dish, some slice, what does |
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19:10 | have to do with the human There's canonical circuits, their canonical rules |
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19:17 | which these circuits operate. And we this in the brain slices and the |
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19:23 | animal brains and in the human brain doesn't mean it does exactly the same |
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19:29 | responsible for exactly the same thing, the principles, some of the principles |
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19:34 | some of the rules, we only these rules from the dish in |
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19:40 | We couldn't have learned these rules by electrodes into human brains and giving them |
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19:46 | that induce seizures in the chair. not possible. So and it's still |
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19:52 | possible. So now this is what tells you. You know this discovery |
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19:56 | vitro cancer molecules. What is Nobody's seen. There's no pathologist |
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20:03 | And you're gonna fight for it for or five years. You're gonna spend |
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20:07 | PhD doing fighting it. And then you're opposed people like inviting you to |
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20:13 | about this molecule and cancer please. know, five years everybody's like no |
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20:18 | artifact. You have to prove people of that. So I have to |
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20:23 | the reviewers that I recorded seizure And I said these are the two |
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20:27 | of cells and all 11 criminal And I said that's not enough. |
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20:32 | we learned that there is this dye Golgi stain right? And Golgi stain |
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20:38 | stay in all the processes. And this experiment inside the ipod I have |
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20:43 | diet that's called neuro biotin. And I'm recording from the cells these cells |
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20:49 | getting filled with the dye. So I finished the recording I have more |
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20:54 | data. I take the slices and them with history chemistry. I reveal |
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21:01 | E di that was entered into the cells and this near Abidjan died. |
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21:06 | like Golgi stain will reveal in full morphology. All of the processes then |
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21:13 | when this white accent that's coming out in this plan. Outside of the |
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21:18 | projecting out and this looks very much the alarm. So morphological e because |
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21:24 | has a certain anatomy dendrites coming out targeting the region there and I still |
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21:32 | publish this paper saying that this is lamb cell until they did a stain |
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21:37 | cells express a specific market called Samata . So to prove the reviewers that |
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21:42 | recorded from all them cells and phenomenal , we have to basically do this |
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21:48 | approach. It's called neuroscience. You have to go for the problem and |
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21:54 | the solution. The technique is just technique, electrophysiology, seismology, micros |
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22:00 | and you know history chemistry, this history chemistry, this is immune, |
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22:05 | chemistry is it has to use antibody that are specific as antibodies are marked |
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22:09 | fluorescent markers. So if it's marked fluorescent marker, you cannot see on |
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22:14 | regular light microscope. And now the it is a fluorescent microscope and con |
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22:19 | that can resolve it so that you have this picture, You're solving a |
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22:24 | , You're going after something. The is just a technique, learn a |
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22:28 | , master it and use it. think the technique is your profession |
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22:33 | you know of course you can be brilliant electro physiologists. All you do |
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22:37 | people do that and it's great. most of the time you use that |
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22:42 | a tool to get to certain answers if that doesn't get you the |
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22:46 | you have to move on to the tool and if you think you're done |
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22:50 | the reviewers are going to send your see these three years of work you |
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22:54 | spend doing you need to do additional doing something else or you're not gonna |
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23:01 | this paper. So what do you ? You don't publish the paper? |
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23:06 | that's one way of looking at Or you go and you try to |
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23:09 | that technique and send the paper back the reviewers and art. It's called |
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23:13 | review. A lot of the publications you see in the scientific world. |
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23:19 | review that means that if some professor something 34 or five other professors from |
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23:24 | the world review it very picky everything compress their name is spelled just like |
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23:33 | sun reviewer paper ended up in somebody's and you must spell their name. |
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23:37 | can get dinged for that pretty You know that's not even talking about |
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23:41 | science and the data. Alright so is a whole whole serious process. |
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23:47 | then would you read mostly in science you read stuff online? It's popular |
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23:54 | a lot of times it's marketing science . Content created by writers that have |
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24:03 | interest or knowledge if their masters in . That's great. But you will |
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24:09 | that even scientific articles and popular literature lot of times are written by people |
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24:14 | maybe have a high school degree. for you when you search for literature |
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24:20 | go to U. H. Libraries use your account and you go on |
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24:25 | pub med search engine. And this where you find peer reviews. I'm |
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24:30 | saying that there's something wrong with writing science in a popular way. I'm |
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24:34 | saying that I'm just saying that process very different of how you publish a |
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24:39 | in a scientific journal under peer review how you publish an opinion or an |
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24:46 | in another journal. And I've done and actually legally enjoy writing more for |
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24:51 | general audiences. Uh And it's a . It's a challenge because I could |
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24:57 | very complex language and write very complex electro physiological biophysical language. But for |
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25:06 | the challenge and more of an interest can I translate it to people that |
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25:09 | understand it or don't have bio one bio two or neuroscience. So anyway |
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25:16 | we did it we did this Now if you go into another part |
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25:21 | the brain this is Neocortex you're gonna that these networks again have phenomenal cells |
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25:27 | parameter cells will be projecting out of local networks and these parameters cells again |
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25:32 | going to be fined by the inhibit inter neurons. And if you stab |
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25:37 | cell here and you inject the One thing to keep in mind is |
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25:42 | stronger the stimulus that higher is the of action potential. So this is |
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25:47 | way in which cells code the strength the stimulus is by a number of |
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25:53 | potentials that get produced. Another way the pattern of these action potentials. |
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25:59 | cell if you inject the current into cell this cell is referred to as |
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26:04 | stuttering cell because if you inject enough for it to fire action potentials it's |
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26:10 | gonna delay, it's gonna take some 2030 milliseconds, 200 milliseconds before it |
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26:18 | action potentials. And when it does doesn't produce them in a continuous |
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26:23 | But rather its starters you can increase frequency of the action potentials if you |
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26:34 | the stimulus. But the pattern, stuttering pattern is still preserved. As |
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26:39 | can see this cell is delayed cell accommodating but it produces a much slower |
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26:47 | of action potentials and it doesn't produce in stutter but rather continuous. It |
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26:53 | to stimulate the south. It just the same frequency. There are other |
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27:02 | that start with fast bursting frequencies and they actually slow down over time. |
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27:08 | you have the stimulus is sustained. the way these cells react is |
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27:20 | This is a bursting cell. This the dialect of neurons. This is |
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27:31 | neurons talk to each other and the of that dialect. The patterns. |
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27:37 | complexity of these patterns comes from the cells because you have a much greater |
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27:43 | of inhibitory cells with much more different unique number and properties capable of producing |
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27:50 | different dialects. So action potential is language and each of these cells speaks |
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27:57 | slightly different dialect. You want cells react to fast frequencies and process them |
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28:02 | a very fast manner. The fastest the fastest neurons in the brain can |
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28:07 | up to 600 action potentials a That's called 600 Hz 600 action potentials |
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28:17 | one second. Some of the cells very, very fast. You need |
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28:21 | because you have some very, very stimuli coming at you visual auditor and |
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28:25 | on. Some cells are slow and function is to introduce another dimension of |
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28:34 | . In this case slow computation and . And these rhythms that produced by |
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28:41 | sounds, they become like an orchestra , like a symphony and an equivalent |
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28:48 | that when you walk in the symphony the orchestra is sitting in the down |
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28:53 | and they're all warming up and it like chaos, all the noises coming |
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28:59 | everywhere. They're warming up. But they produce coherent tune. Then the |
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29:06 | violence starts going, you know, timpani starts drumming in the back |
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29:13 | you know, the cello is come the woodwind instruments so on and it |
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29:18 | a song. Now, that song have to be uh all synchronous and |
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29:26 | can have chaotic music too, that's , chaotic music. But from this |
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29:33 | language of the south, the whole is going to produce a network activity |
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29:37 | going to produce a certain frequency oscillation the network. Some of the things |
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29:42 | going to go up and fire some the South are going to get inhibited |
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29:47 | this kind of oscillation and the network then get communicated onto the adjacent networks |
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29:52 | the projection parameter south. This is setup that I used to work on |
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30:01 | a postdoc. I did my PhD Louisiana State University Medical Center in New |
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30:09 | in the nineties and then I moved uh my first postdoc position which was |
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30:17 | johns Hopkins University Mind Brain Institute. then my second postdoc which is this |
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30:24 | is from the second postdoc and we it rigs here in texas and Louisiana |
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30:29 | stand for something else. Either go on the rigs the rigs. This |
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30:34 | a different kind of rigs. It's on the rig. It's electrophysiology |
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30:39 | This is my second postdoc at George University which is in Fairfax Virginia about |
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30:45 | an hour from D. C. was in 2000s and my PhD work |
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30:53 | focused on excited and inhibitory synaptic transmission the development of the visual system. |
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31:01 | first postdoc focused on plasticity, individual in the cortex and my second postdoc |
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31:10 | on epilepsy and neurological disorders, abnormal activity during events like seizures. So |
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31:20 | is a slice in there. Believe or not sitting underneath this lands and |
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31:25 | told you that these slices are being . They're being fooled that they're still |
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31:28 | of the brain with cerebrospinal fluid and that is being supply to them. |
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31:34 | then you know there's only probably you 100 people, maybe 200 crazies like |
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31:41 | . They would try to stick like or three cells at the same |
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31:45 | Four electrodes underneath the microscope run out equipment rather 10 older. So these |
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31:52 | electrodes that I was showing you these electrodes here. They're connected these micro |
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31:59 | electors actually extend from this one micro extend all the way into these pre |
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32:07 | heads we call them. And then pre amplifier head holders and holders have |
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32:14 | manipulators, you can move things PS like nanometers or less distances. This |
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32:22 | is floated. So anything that moves the table, anything that moves outside |
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32:29 | table is floated, it's completely It takes about an hour to an |
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32:34 | and a half to get an animal put an animal asleep to get animals |
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32:39 | prepare slice and place the slice under and then once you have it |
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32:45 | you better be sitting on that chair at least 6 to 10 hours. |
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32:49 | that's the kind of and then you about 45 minutes of Queensland. And |
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32:54 | semi sterile environment. So every day every night clean. These rigs are |
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32:59 | just spotless with hot water you can't out, we can't use too much |
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33:03 | a hot water because we have instrumentation plastics and glues that So it's a |
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33:10 | of effort to try to get these that I was telling you about. |
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33:14 | takes a whole day. And if were good you would get three cells |
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33:18 | day. If you were good you get a triple patch in one |
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33:23 | If you were amazing, you would a quadruple patch ourselves and that may |
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33:29 | you a whole week to do And so we did it for a |
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33:34 | and I don't think I'm gonna do anymore. But it's again very interesting |
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33:40 | which teaches you a lot of stuff a lot of troubleshooting and problem shooting |
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33:46 | you have to realize is that this is connected to about two stands here |
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33:51 | are full of amplifiers, more sophisticated and current stimulators, current generators, |
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33:59 | screens and so on neuroscience. so this is how we study |
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34:08 | we study their activity. And now going to start talking about glia And |
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34:14 | gonna end at 12:45 or make sure I clear out of here before the |
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34:19 | professor comes first leo Blue and greek thought to play a supportive and insulating |
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34:28 | for neurons. But apart from supporting insulating all the neurons are very actively |
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34:36 | in regulating your own all transport neuronal genesis the amount of neurotransmitters that neurons |
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34:45 | use and there's synaptic signaling and many different features. So the some type |
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34:55 | glia that we're going to discuss. of them is micro glia microglia are |
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35:01 | they're the smallest real elements are also most mobile real elements. They're responsible |
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35:08 | cleanup damage, repair, scavenging, for debris. Clean up the |
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35:18 | So, if you recall in your your class folder, you have this |
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35:32 | class lecture documents. And you will that there are some links. Some |
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35:40 | these links. So, I've got essay written. So now I'm gonna |
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35:42 | you how I use Graham early to . Okay, so here's my essay |
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35:47 | the ads and I don't that's not point. All right. What? |
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36:03 | , let's see what we're looking at . So, first of all, |
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36:06 | is this? It's a timescale in . What is this? It's uh |
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36:14 | μm in space distance space bar. And what we have here are the |
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36:26 | and all of these cells are specifically glial cells. So there is a |
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36:32 | marker because because cells expressed our specific , we can also tag them. |
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36:38 | we labeled all microbial cells. Scientists wanted to go do something someplace not |
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36:46 | . Uh and there is an Boom right here in the middle and |
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36:54 | you're seeing, what you're seeing within . We finished within minutes following the |
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37:04 | . What does marco glial cells due start extending their processes that we |
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37:11 | So the other parts of the body have like activated activation of macrophages in |
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37:16 | brain is microbial cells is injury, inflammation. Microbial cells get activated, |
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37:23 | become mobile that starts seek out the they also involved in. The cytokine |
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37:30 | the pro inflammatory cytokine regulation. And essentially your neuro immune neuro uh inflammatory |
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37:40 | that you would see. And michael salsa involved in in in these processes |
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37:46 | the most mobile elements. And besides their processes, he actually over time |
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37:52 | , you can see that selma's also over certain periods of hours of |
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38:00 | It's not only the processes that extend so must actually move through the brain |
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38:07 | into the location where they're being called . This is micro glial cells. |
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38:17 | cells that will talk in greater detail we'll come back and talk to them |
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38:21 | . As astrocytes and the astra sites involved in. We call them originally |
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38:28 | chores. But now we know that involved in regulating the amount of |
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38:33 | So they regulate the amount of neurotransmitter is available to neurons. They're involved |
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38:39 | regulation of synaptic plasticity and synaptic communication they are responsible for regulating the local |
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38:47 | . So make sure that there isn't much of the neurotransmitters or too many |
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38:50 | the ions of a specific kind that risen and astrocytes will be able to |
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38:56 | this abnormal chemical changes locally during early . Our neurons are not born |
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39:07 | But rather they're born in specific parts the brain and from those specific parts |
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39:13 | the brain. They migrate. That that visual neuron that is in the |
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39:18 | visual cortex, in the occipital lobe . It's not born here. It |
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39:25 | him. It's born in specific areas the brain. We won't be discussing |
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39:31 | that are more internal. And from areas of the brain my migration starts |
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39:37 | neurons will migrate until they find the destination until they find their cortex there |
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39:45 | , right their city and they find neighborhood which is their circuit and then |
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39:50 | find their mailbox which is them. that's that neuron that found its mailbox |
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39:57 | the area. And to do this and process outgrowth for neurons. You |
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40:04 | the other type of cells. And are radial glial cells. And what |
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40:13 | shown here is something super interesting. is a neuron and this is a |
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40:21 | glial cell and this neuron now hugs glial cells. It becomes membrane and |
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40:31 | plasma continues with the cell. The infuses and then uses it as a |
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40:40 | this membrane to move and migrate that thoughts. So you'll have radio glee |
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40:51 | . Oops. I don't know what is. I don't know what that |
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40:57 | . Uh you have radio real cells they ate in this migration. This |
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41:03 | another example of neuronal migration. In case it's without radio real cells. |
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41:11 | can see that there's a lot of going on. A lot of touching |
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41:16 | on, fusions, separations and movements different directions as the neurons are migrating |
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41:24 | they're using in many cases radial glia their guide sort of as a |
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41:29 | The latter as a ladder to climb to layer two in the cortex to |
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41:35 | off to layer forms stay there and glial cells can also become neurons |
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41:42 | So they're almost like a multi pluripotent . So growth factor release uh glial |
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41:55 | can release neurotrophic factors that influence slower . And in general if you're thinking |
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42:06 | is this your cup? I was wondering if anyone found my welcome to |
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42:15 | and look. So uh growth back released like neurotrophic factors also can influence |
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42:23 | slow growth factor at least like slow . Uh And uh in general when |
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42:33 | thinking about neurons, neurons produce action and glia do not produce action |
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42:41 | Glia communicate with much slower calcium waves they're active. They have membrane potentials |
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42:50 | they do not produce these fast action that neurons do. And now you |
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42:55 | envision that you almost have two different scales. You have fast action potentials |
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43:04 | neurons fast neural transmission and communication between and then you have this other temporal |
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43:11 | which is slower which is in minutes micro glia which is dealing with inflammation |
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43:19 | is dealing with metabolism and production of and you have these temporal scales operating |
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43:27 | the same time. Very fast neuron neurons, slower glee are taking care |
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43:33 | stuff too And so there are different but very important roles in the brain |
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43:41 | general glia control formation of new synapse number migration of neurons and synaptic |
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43:51 | . Also so many different functions can ascribed to clear. For Myelin Nation |
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43:57 | have Myelin Nation in the P. . S. Peripheral nervous system. |
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44:01 | have Myelin Nation and the C. . S. And this is you |
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44:05 | actually there is a difference between the to peripheral nerves right and nerves in |
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44:10 | hands and and your legs that you regain. You can regain feeling in |
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44:16 | nerves. These nerves can partly repair depending on the damage the physical damage |
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44:21 | the nerve or some other disease like C. N. S. Will |
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44:28 | regenerate. The nerves will not It's a different chemical environment, it's |
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44:34 | different installation and P. M. . Each one of the nodes of |
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44:39 | which comprises the smiling nation of the . Each one of the nodes of |
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44:45 | is a single swan saul with nucleus is wrapping around to form a single |
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44:52 | in the C. M. You have other types of cells illegal |
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44:56 | side so there's illegal Denver sides instead one salad forming one segment, one |
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45:03 | of illegal Denver side is going to out. That's going to do this |
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45:08 | of a weird wrapping around from the to form that myelin segment in between |
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45:15 | segments. You have nodes of wrong and in those of Ron beer. |
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45:20 | action potential that gets produced at the initial segment. This action potential will |
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45:26 | regenerated each note of Ron beer so when it reaches its external terminal it's |
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45:33 | same amplitude and the same dynamics as was from its origination point. |
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45:41 | so my elimination here and you'll see sheets wrapping around nodes of reindeer. |
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45:48 | have mitochondria and you'll have energy You'll also have a lot of both |
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45:53 | sodium and potassium channels. That's what action action potential. And this is |
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45:59 | regenerates action potential at each note of . And so you will know |
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46:03 | A lot more about that too. had a very interesting question yesterday. |
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46:09 | do cells know when to stop the segment? Uh and maybe you'll get |
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46:17 | of the clues and some of the in the subsequent slides. But you |
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46:22 | pick up there's a finite size for process. In other words, this |
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46:27 | from a legal tender side cannot be one yard wide or one micro meter |
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46:35 | . It's gonna be about one to micrometers wide. So daniel read |
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46:43 | you have the limitation in size. does it precisely know that? It |
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46:49 | to stop at the note of wrong . We don't don't exactly know that |
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46:54 | there is selling silver recognition. There protein protein interactions that we guide these |
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47:00 | . Uh And we'll talk about some these and in particular we'll talk about |
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47:07 | with respect to myelin compaction diseases and elimination diseases. So it turns out |
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47:15 | this compaction is wrapping around is mediated at least seven related podiums which are |
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47:23 | this. This this myelin compaction. or myelin associated glycoprotein is one example |
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47:32 | the seven proteins. And Maggie is for initiation of Myelin Nation. That |
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47:37 | that you have proteins that are responsible initiation proteins. Um South south and |
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47:44 | protein interactions are responsible for wrapping and there are those that are responsible for |
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47:51 | . In addition the level of the of the proteins is very important. |
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47:58 | what happens in in some of the Myelin Nation diseases and what I have |
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48:05 | is Encephalomyelitis. Written on top We already know Encephalitis is an infection |
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48:12 | inflammation of the brain. Encephalomyelitis is condition that that infection and inflammation in |
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48:19 | brain can actually cause de milo And there are models. Animal models |
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48:26 | so we can recreate this D Myelin with viral infections. But we also |
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48:34 | to model not just Encephalomyelitis which is real thing. People get encephalitis. |
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48:39 | you heard of Syphilitic ticks? You not be from one of those states |
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48:45 | ticks are rampant. My cousin had twice in the last three years because |
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48:52 | stays in the countryside by the lake ticks of breeding every spring and he |
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48:57 | bit like five or six times and ended up in a coma in the |
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49:02 | with encephalitis. So we all know most dangerous animals in the world are |
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49:10 | bugs, little mosquitoes. Little ticks carry all of these diseases. You |
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49:16 | . So but so so you want replicate and you can do that. |
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49:19 | can infect the animal, You can the virus into animals. You can |
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49:25 | the neuro degeneration and do my elimination and you can observe the symptomology of |
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49:31 | . Perhaps one of the most uh diseases of demonic nation and the |
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49:37 | N. S. It's multiple It's here in yellow multiple sclerosis. |
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49:44 | multiple sclerosis can be linked to chromosome mutations. You have to have recessive |
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49:52 | to that Palios. And one of symptoms of multiple sclerosis disease is is |
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50:00 | and sometimes convulsions. Okay so that's is multiple sclerosis. Demon eliminating |
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50:07 | But is multiple sclerosis autoimmune disorder Your body starts looking at myelin as a |
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50:16 | invader and starts destroying its own auto immune disorder, developmental onset and |
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50:27 | . See onset typically in the 30s up why? Great question. All |
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50:35 | and now you can have a disposition cancer. Alzheimer's never forming outside triggers |
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50:42 | mutations. Second Aliyah mutated. Why that have genetic predispositions are likely to |
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50:53 | diseases and why some are no I know in science. You want to |
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50:59 | at a human condition like this and want to try to replicate as much |
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51:04 | the human condition in an animal So when people tell these an animal |
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51:09 | , not because you're just taking around doing something, you're gonna have a |
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51:16 | . You're gonna create a genetic mutation the animal. And you can create |
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51:20 | that are called transgenic animals. That you have a mutation in a specific |
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51:28 | and you can have formation uh the nation, okay. And this animal |
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51:36 | a shiver animal. So it will tremors and convulsions that you would see |
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51:42 | M. S. So a Mass demolish nation can take place in many |
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51:47 | parts of the brain. You already that certain parts of the brain are |
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51:51 | for executive function. Other parts of brain responsible personality traits, memory, |
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51:57 | , where that'd amalgamation happens will affect particular function. If it is affecting |
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52:04 | cortex, motor pathways, speech you will have problems with those particular |
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52:13 | . So when you're doing a you're doing a genetic model, you |
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52:19 | to replicate what's in the genes. doing a cellular model. Because you |
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52:26 | a mile the nation, you're doing behavioral of symptomatic observation on these |
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52:32 | Yes, they have tremors, they seizures. You're trying to replicate and |
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52:37 | as much of a human condition in animal as possible because that allows you |
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52:45 | to say whether you have a good or a bad model if you inject |
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52:50 | virus into the brain and you caused , that's not a good model for |
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52:56 | mess necessarily. But it's a great for viral infection and inflammation driven desalination |
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53:04 | this. I'll get to your question this final image here. This animal |
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53:10 | transected with normal gene. So it's gene transfer action sort of, you |
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53:16 | think of the future gene therapies in way and there's a partial restoration of |
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53:22 | of the myelin. So the gene important, whatever gene is producing is |
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53:28 | protein that that that helps preserve the and that stops the attacks and all |
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53:34 | immune response or something like that. all very important. Yes. |
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53:43 | so it's a different circuit. it's a it's a different disease. |
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53:51 | your question is very good because I mentioned to you that certain symptoms and |
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53:59 | will be overlapping between diseases. in Parkinson's, you have what are |
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54:05 | typical Parkinson IAN bombers, the pathology the disease is that from the neural |
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54:13 | that are involved is different. It's larger diseases, dopamine impairment. |
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54:22 | and sometimes parking Sony and tremors can into an iconic seizures, even a |
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54:30 | and that symptom you would observe in types of epilepsy is also, and |
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54:34 | why I say that there's overlap between . But you're correct for Sony in |
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54:39 | , but also if you created an model of Parkinson's, you would be |
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54:44 | a different part of the brain targeting dopamine ergic circuit. Using a different |
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54:49 | for Parkinson's. There's actually a very chemical model too. And will allude |
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|
54:55 | that. I think in this course not sure if I talk about in |
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54:57 | course or cellular neuroscience. Very And then in the periphery you have |
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55:06 | type of myelin dysfunction of the myelin . And that's shark lot narrative museums |
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55:13 | it's a developmental disease. So that it happens during early development. It's |
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55:21 | chromosome 17. You have a duplication chromosome 6 17. In this case |
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55:27 | have a over expression of this N. P. Two, two |
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55:35 | people that have uh this mutation they in the periphery partial loss of |
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55:43 | Now, if your peripheral nerves are signaling correctly to your lower limbs from |
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55:49 | spinal cord, not sending the correct during the development, that means there |
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55:54 | no proper contraction of the muscles as muscles shape themselves and the bones grow |
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56:01 | the development. A lot of people have deformities in their lower limbs. |
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56:06 | will have problems with walking and with and you can see that's mostly affecting |
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56:11 | lower limbs. There's no cure for disease. You can detect it as |
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56:18 | as possible and place people into the braces and physical therapy so helps them |
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56:26 | their bones and their gay as a of the development, obviously it depends |
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56:31 | world you live in and what medical you have around you and diagnostics. |
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56:36 | know, if you're somewhere in the of nowhere, 10 hours away, |
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56:41 | surrounded by the desert or by the , you know, this is something |
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56:47 | you may not understand or the families understand this condition early on, you |
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56:52 | not see it. And I think kid is working, walking funny or |
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56:56 | like that. So it all very depends these are two more diseases that |
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57:02 | adding actually three because encephalomyelitis, but the perspective of a human disease you |
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57:09 | have and so for myelitis, but sclerosis is important to take notes and |
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|
57:17 | cut marinated disease. And finally this puts into a great perspective the cells |
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57:23 | we're talking about the good emphasize astra and you can see that astra size |
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57:29 | be controlling synopsis and Sinatra genesis, transmission and also have their end feet |
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57:35 | the micro capillaries forming part of the brain barrier have the micro glial |
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57:41 | They have these dependable cells that are surplus final fluids from interstitial fluids. |
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57:47 | dependable cells are potentially potent also can other types of wheel and their own |
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57:54 | and the last slide in this lecture on blood brain barrier and I don't |
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58:00 | to just do it in one But I want to remind you that |
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58:04 | brain barrier is a good thing because in your blood doesn't always cross freely |
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58:08 | your brain and you don't want that when you drink a big Assume |
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58:13 | you don't want all of these all of the things you consume going |
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58:17 | your bloodstream, going into your brain the end to feel yourselves will form |
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58:22 | junctions, parasites will surround them, , surrounding all of these checkpoints. |
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|
58:29 | the substances crossing into the brain. we talked about how during COVID-19 you |
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58:34 | inflammation and breaches in the blood brain and now the viruses and other molecules |
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58:39 | pass into the brain much easier. the most part this is a really |
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58:45 | protective barrier and the things that get the brain that have to be |
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|
58:49 | Maybe they have to have transporters that them across. Maybe they're like facility |
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58:54 | means that remembering soluble and the cross through these membranes into the brain. |
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59:00 | the same time. When you think neurological drugs and I'll leave you with |
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59:05 | stock for for the labor day most of the pain killers uh medicines |
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59:13 | we consume, we ingest. And we ingest 200 mg of ibuprofen, |
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59:19 | doesn't mean 200 mg of ibuprofen and helping us with a headache, a |
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59:24 | of it is gonna get into the and then a fraction of it is |
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59:28 | cross through the blood brain barrier. with some drugs it's a problem. |
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59:33 | you will see commercials that somebody's trying treat their migraine. But then the |
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59:39 | will list are you having suicidal Are you having diarrhea? Are you |
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59:43 | over and and as you seem bleeding your abdomen, all of these |
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|
59:49 | Why? Because in order to affect brain condition neurological condition effectively, sometimes |
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59:55 | drug does this are quite high that swallow and they cause the side effects |
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60:01 | the systemic effects that people can experience and another stuff like that. So |
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60:08 | we come back on a week from , on thursday, so again, |
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60:14 | have Tuesday off and I urge you review all of the material on |
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60:18 | It's a good halfway point. When come back, I will tell you |
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60:23 | how would you want to design a pharmacological drug? What are some of |
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60:28 | features that you're gonna have to think for that drug to be effective for |
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|
60:32 | drug to effectively across the blood brain . And maybe maybe even dream of |
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60:39 | a drug that will be self One of those 21 setbacks of |
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60:47 | Think of a way you would target drug to one of those 21 subtypes |
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|
60:52 | . How would you go about Okay, thank you very much. |
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60:55 | I will see you all next thursday on zoom. I'm gonna exit |
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61:06 | I save the lecture. Please email guys if you have |
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