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00:02 this is Lecture four of neuroscience and ended up talking about how cells receive

00:09 inputs and they received inhibitory inputs and neurotransmitters glutamate and the inhibitory neurotransmitters,

00:17 , which is gamma immuno butyric They're both amino acid neurotransmitters and the

00:23 1000 neurons can receive hundreds thousands tens thousands of excitatory glutamate ergic inputs.

00:31 , ergic synopsis glutamate will try to the south, will try to de

00:37 them and make more positive charge inside south, telling the south to fire

00:42 action potential to be active inhibitory Gaba binding to the inhibitory synapses in this

00:50 will hyper polarized this neuron, adding negative charge into this neuron, telling

00:56 neuron to stay the essence or silent to fire an action potential not to

01:03 that information into this interconnected network. most of the synopsis is Ramona alcohol

01:12 hypothesized early on form of dendrite dendritic and so Mazz and most of the

01:19 synopsis earned. And dendritic spines and abnormal formation lost number densities positioning of

01:26 spines can result in a more severe to where fragile lacks. It's actually

01:33 genetic disease that ends up in severity that depends on the damage to the

01:39 , which ends up damaging the protein is responsible for regulating other genes in

01:49 these dendritic spines and see how different the two disorders are that we've discussed

01:58 we then started talking about The fact in the 19th and 20th century we

02:09 understanding what are different parts of the , how they look differently with the

02:14 that we used were the scientists used we also realized that there are different

02:21 of neurons and different subtypes of And so we started discussing how one

02:28 sub classify or subtype these different the of neurons. And so we talked

02:35 morphological descriptions, some salsa unit polar , pseudo unipolar. This is our

02:41 root ganglion cells in the spinal cord cells in the retina that you learn

02:46 . When we study the visual system neuron which is multipolar coming out of

02:51 ventral side of the spinal cord is . The muscles have most of the

02:56 in the cns and the cerebrum are . One of the most famed cells

03:01 the excited projection parameter will sell because looks like a pyramid and it has

03:06 apex and an ethical done drive. has the base and basal dendrite has

03:11 axon that interconnects other regions of the . And you have this very Sophisticated

03:18 . The cells of the cerebellum that have a 250,000 synapses. Therefore it's

03:24 important to have precise anatomy and function the synopses of the downgrades and the

03:29 expires so that these neurons can integrate process that information in a very fast

03:36 and communicate that information. And once looked at classifying neurons based on the

03:45 . We said there's also classification whether projection cells or whether local into

03:50 And we said that projection cells like cells, they will project out of

03:55 networks into the adjacent networks. They communicate, excited for information there.

04:00 ergic cells. Most of the inter are local network cells and their inhibitory

04:07 means they release Gaba, gaba ergic . So excitability, excitatory versus inhibitory

04:14 specific markers which are very important. get back to that in the second

04:18 neurotransmitters, neural peptides, the secular , receptor membrane proteins, trans membrane

04:27 . They all can be slightly differently by these different subtypes of cells.

04:32 we also need to know that information importantly, after we understand the location

04:39 the cells, their morphology, what they express which is also their

04:45 We also want to trace their electro properties which is the action potential,

04:51 properties, passive number of properties which resting membrane potential and active member and

04:56 of these neurons, which is these fast situations, 1 to 2 milliseconds

05:01 duration of approximately 100 million volts in . So the first one was published

05:07 1939, but Hodgkin and Huxley. we talked about how difficult it would

05:16 been to do these experiments and then more so how difficult it is to

05:22 what you've done to people that were in the room and to convince them

05:27 the absence of the modern technologies such um cell phones and computers.

05:35 And we ended here with the last in this very important network. It's

05:42 very important network because it is a well studied network. It's a it's

05:49 popular structure in the brain. A of people know about it the

05:56 if you're in psychology people talk a about hippocampus too. So if you

06:01 psychiatry, if you and other memory sciences or if you're in the

06:07 , computational neuroscience engineering, this is very good circuit to learn because there

06:16 a lot of features of this circuit we call canonical features of this circuit

06:22 the hippocampus. That means that this of arrangement is going to be likely

06:30 in another part of the brain and circuit. There are certain rules by

06:34 these neuronal circuits function. Hippocampus is part of the limbic system and the

06:40 is responsible for memory formation, memory and also emotional memories and emotional processing

06:49 general. It doesn't mean that memories stored in hippocampus in this one

06:55 Memories are actually semantic memories in particular hippocampus is responsible for encoding are widely

07:02 throughout the cortex. That's why if have the damage to one part of

07:06 brain, you have a certain type damage but it doesn't mean like we

07:12 about language areas. If you want take out somebody's language ability you have

07:16 take many different parts of the brain them to completely lose that ability.

07:22 now in hippocampus you have predominantly three stratum and stratum orients starting from the

07:32 is Farrah middle cell layers stratum of layers. So it's a parameter layer

07:39 90% of these parameters all cells, of these phenomenal cell bodies. Selma's

07:46 live in this lake. This structure a three layered structure and a lot

07:51 times it's referred to as our key which is archaic cortex. It's archaic

07:58 versus neocortex which is the cerebral neocortex a six layered structure. And hippocampus

08:05 actually going through some sort of a evolutionary development and I think it's trying

08:12 become neocortex also. It's trying to itself into potentially sick slave structure to

08:18 that's what happens with activity with stimuli genetic uh Attrition and selection if you

08:26 natural. Uh But so we have circuit and what are the teachers of

08:33 circuit. You have these parameters ourselves this parameter cells look exactly the

08:39 90% live in the same layer. projection excited for ourselves. That means

08:45 will project their axons outside of the into other parts of the brain.

08:52 of the biggest projections from here goes interim final cortex. So these are

08:58 ourselves. Some of them have their in audience and about 10% either than

09:06 . If you were to stick an inside the cell it will produce the

09:11 Exactly pattern of action potentials. If is still pending positive which is

09:16 D. Plus or co dependent The only distinguishing factor here between these

09:22 is an intracellular sell market and because have a slightly different expression the different

09:29 cellular marker different intracellular molecule that they . Their physiology is different. They

09:36 the second step time from excitatory Other than that they look the same

09:42 they fire the same patterns of action all parameter cells in the hippocampus and

09:51 job was to excite from this part the hippocampus. Other parts of the

09:58 or other parts of the brain. boring but we're not boring. And

10:06 happens is that we have a lot different complex sensors stimulate and coming at

10:11 with different frequencies the light is coming hitting us with wavelengths 407 100 nanometers

10:18 is coming and hitting our ear drums frequency 10 hertz to 40 kilohertz is

10:25 audible human range tapping car vibrations. our sensors stimuli people shouting at

10:32 somebody giving a good ideas, bad upsetting you. You know all of

10:39 requires complexity. And if you just one and two subtypes of excitatory cells

10:45 doesn't seem very complex. And this networking Hippocampus is three lead structures fairly

10:54 but it's also fairly complex when the arises from the 21 subtypes of inhibitory

11:03 . So these other cells in the . They all express and release

11:08 Their inhibitory they release Gaba they're into which means that they will stick around

11:16 the circuit and they will try to the activity of criminal cells in each

11:22 . But ultimately they will sculpt and train the type of physiological activity.

11:30 prom. It'll cells are going to able to communicate into the adjacent interconnected

11:36 . So their role locally here is try to sculpt whatever pattern of activity

11:43 the parameter cells are communicating or shut parameter cells because their inhibitory cells and

11:49 them quiet. These inhibitors south are throughout the three layers. Someone that

11:57 inhibited ourselves again, they live in same layer like two and four.

12:03 have the same pattern here in These dead rights that are going

12:10 These cops yellow cups are inhibitors And one of the things we want

12:17 know is where are these inhibitors synapses on the promenade cells. Inhibition is

12:23 lot more effective when it's targeting the and the accident initial segment because this

12:29 the integrated region of the south. you can actually influence whether it's going

12:34 find action potential or not. So and four has this inhibitor synopsis and

12:40 all target the soma is here at pyramidal layer south. And the only

12:46 again between the students themselves is that of them expresses the marker P.

12:52 . Which stands for approval document and one expresses other markers which is

12:56 C. K. And B. three. So you won't be responsible

13:00 what type of sub type of cell two and four express which marker.

13:05 the take home message is that these subtypes of cells even if they look

13:09 same and have the same morphology the location and even the same number and

13:15 properties that can still be distinguished by intracellular Uh cell markers that are unique

13:21 makes them a different subtypes of This is from 2008. So it's

13:27 likely if I look at the latest from the inhibitor subtypes of Hippocampal

13:34 This number may be higher than 21 predict it's probably 26 or 27.

13:40 at some point there was a discovery two or three different subtypes of different

13:45 in Hippocampus and in the cortex almost a on a monthly basis. Uh

13:52 you can see that some of these cells will target integrated regions. Some

13:58 the synopses, inhibitory synapses will target of the south. Others will target

14:06 output of themselves. But the most is that you can target the integration

14:12 the cell makes up its mind. the cell makes up its mind and

14:16 an action potential. You can maybe out outfit not as effectively though is

14:23 the formation of that output. So is something I used to do for

14:29 very long time. It's called patch wholesale electrophysiology uh also a lot of

14:38 uh referred to as multiple wholesale recording multiple simultaneous real time patch clamping.

14:48 uh I've done it for a long like I said um let's see if

14:59 , okay. So what I did I explained to you that in the

15:03 days you have to stay in the to visualize it. But then I

15:06 we had these infrared cameras and microscopes you can put a slice of the

15:10 underneath and you can actually visualize these . So I was recording in hippocampus

15:16 I approach these neurons that attend microns diameter. I targeted these neurons with

15:23 electrodes that are approximately one micrometer in diameter at the tip or less.

15:30 are borosilicate glass electrodes. The electrode have inter cellular solution in them.

15:36 inter cellular solution should be exact same very similar to what is inside the

15:43 . So the electorate solution should be same as the inter cellular neuronal solution

15:50 you essentially can poke these cells and can stimulate them. So assume that

15:55 cell on the right looks like a cell. And I inserted the electrode

16:00 the cell and I stimulated the cell I increased the stimulation. The second

16:06 of stimulation. So I'm actually producing current in this electrode, pumping positive

16:12 . I'm pretending a big excitatory input this electrode making the cell fire.

16:18 I'm giving it a big input and what the output is going to

16:22 And finally on this third stimulation and a few action potentials and then I

16:31 the stimulus is stimulated even more, more positive current flowing in and the

16:38 response now with this pattern of action and this is I know it's something

16:46 parameter cells, this is the dialect parameters self speak, the action potential

16:51 also patched the cell on the left I said you know what that cell

16:57 the word was located and more than saw about it and all of the

17:02 planes you're seeing a one focal I said I think that cell is

17:06 interneuron and I had a hypothesis that cell is a particular type of

17:12 this number seven which stands for O lam cells. Orients like and I

17:18 like them because they had these horizontal rides. So we picked them out

17:24 the slices and I inserted electorate in cell and I produced the same stimulus

17:31 that left, sell the same amount stimulus has been normalized for other pe

17:36 in the number right? As on right. And when I give it

17:41 enough stimulus, this cell responded with fast frequency of action potentials that it

17:50 it more stimulus firing it not really that frequency of firing. And so

18:00 knew that that is not a phenomenal but I did a more of experimentation

18:06 this. This is not a hunt self specific subtypes. This work was

18:11 understand with different subtypes, neuronal subtypes doing during seizure like activity in

18:17 My main question was which South starts in the brain or in the

18:25 So the answer I found is that ourselves, start seizures, inhibitory cells

18:33 to abnormal synchrony of excited to and inhibitory cells fail and allow for

18:38 excitation to run away and propagate and to other parts of the brain.

18:44 this was in vitro in a And, you know, people didn't

18:48 that this kind of a pattern exists uh then people about 23 years

18:56 I saw the same pattern in humans epileptic brains and inhibitory into neurons being

19:01 active at the start of the So that's what you can sometimes

19:06 it's like, what is this? dish, some slice, what does

19:10 have to do with the human There's canonical circuits, their canonical rules

19:17 which these circuits operate. And we this in the brain slices and the

19:23 animal brains and in the human brain doesn't mean it does exactly the same

19:29 responsible for exactly the same thing, the principles, some of the principles

19:34 some of the rules, we only these rules from the dish in

19:40 We couldn't have learned these rules by electrodes into human brains and giving them

19:46 that induce seizures in the chair. not possible. So and it's still

19:52 possible. So now this is what tells you. You know this discovery

19:56 vitro cancer molecules. What is Nobody's seen. There's no pathologist

20:03 And you're gonna fight for it for or five years. You're gonna spend

20:07 PhD doing fighting it. And then you're opposed people like inviting you to

20:13 about this molecule and cancer please. know, five years everybody's like no

20:18 artifact. You have to prove people of that. So I have to

20:23 the reviewers that I recorded seizure And I said these are the two

20:27 of cells and all 11 criminal And I said that's not enough.

20:32 we learned that there is this dye Golgi stain right? And Golgi stain

20:38 stay in all the processes. And this experiment inside the ipod I have

20:43 diet that's called neuro biotin. And I'm recording from the cells these cells

20:49 getting filled with the dye. So I finished the recording I have more

20:54 data. I take the slices and them with history chemistry. I reveal

21:01 E di that was entered into the cells and this near Abidjan died.

21:06 like Golgi stain will reveal in full morphology. All of the processes then

21:13 when this white accent that's coming out in this plan. Outside of the

21:18 projecting out and this looks very much the alarm. So morphological e because

21:24 has a certain anatomy dendrites coming out targeting the region there and I still

21:32 publish this paper saying that this is lamb cell until they did a stain

21:37 cells express a specific market called Samata . So to prove the reviewers that

21:42 recorded from all them cells and phenomenal , we have to basically do this

21:48 approach. It's called neuroscience. You have to go for the problem and

21:54 the solution. The technique is just technique, electrophysiology, seismology, micros

22:00 and you know history chemistry, this history chemistry, this is immune,

22:05 chemistry is it has to use antibody that are specific as antibodies are marked

22:09 fluorescent markers. So if it's marked fluorescent marker, you cannot see on

22:14 regular light microscope. And now the it is a fluorescent microscope and con

22:19 that can resolve it so that you have this picture, You're solving a

22:24 , You're going after something. The is just a technique, learn a

22:28 , master it and use it. think the technique is your profession

22:33 you know of course you can be brilliant electro physiologists. All you do

22:37 people do that and it's great. most of the time you use that

22:42 a tool to get to certain answers if that doesn't get you the

22:46 you have to move on to the tool and if you think you're done

22:50 the reviewers are going to send your see these three years of work you

22:54 spend doing you need to do additional doing something else or you're not gonna

23:01 this paper. So what do you ? You don't publish the paper?

23:06 that's one way of looking at Or you go and you try to

23:09 that technique and send the paper back the reviewers and art. It's called

23:13 review. A lot of the publications you see in the scientific world.

23:19 review that means that if some professor something 34 or five other professors from

23:24 the world review it very picky everything compress their name is spelled just like

23:33 sun reviewer paper ended up in somebody's and you must spell their name.

23:37 can get dinged for that pretty You know that's not even talking about

23:41 science and the data. Alright so is a whole whole serious process.

23:47 then would you read mostly in science you read stuff online? It's popular

23:54 a lot of times it's marketing science . Content created by writers that have

24:03 interest or knowledge if their masters in . That's great. But you will

24:09 that even scientific articles and popular literature lot of times are written by people

24:14 maybe have a high school degree. for you when you search for literature

24:20 go to U. H. Libraries use your account and you go on

24:25 pub med search engine. And this where you find peer reviews. I'm

24:30 saying that there's something wrong with writing science in a popular way. I'm

24:34 saying that I'm just saying that process very different of how you publish a

24:39 in a scientific journal under peer review how you publish an opinion or an

24:46 in another journal. And I've done and actually legally enjoy writing more for

24:51 general audiences. Uh And it's a . It's a challenge because I could

24:57 very complex language and write very complex electro physiological biophysical language. But for

25:06 the challenge and more of an interest can I translate it to people that

25:09 understand it or don't have bio one bio two or neuroscience. So anyway

25:16 we did it we did this Now if you go into another part

25:21 the brain this is Neocortex you're gonna that these networks again have phenomenal cells

25:27 parameter cells will be projecting out of local networks and these parameters cells again

25:32 going to be fined by the inhibit inter neurons. And if you stab

25:37 cell here and you inject the One thing to keep in mind is

25:42 stronger the stimulus that higher is the of action potential. So this is

25:47 way in which cells code the strength the stimulus is by a number of

25:53 potentials that get produced. Another way the pattern of these action potentials.

25:59 cell if you inject the current into cell this cell is referred to as

26:04 stuttering cell because if you inject enough for it to fire action potentials it's

26:10 gonna delay, it's gonna take some 2030 milliseconds, 200 milliseconds before it

26:18 action potentials. And when it does doesn't produce them in a continuous

26:23 But rather its starters you can increase frequency of the action potentials if you

26:34 the stimulus. But the pattern, stuttering pattern is still preserved. As

26:39 can see this cell is delayed cell accommodating but it produces a much slower

26:47 of action potentials and it doesn't produce in stutter but rather continuous. It

26:53 to stimulate the south. It just the same frequency. There are other

27:02 that start with fast bursting frequencies and they actually slow down over time.

27:08 you have the stimulus is sustained. the way these cells react is

27:20 This is a bursting cell. This the dialect of neurons. This is

27:31 neurons talk to each other and the of that dialect. The patterns.

27:37 complexity of these patterns comes from the cells because you have a much greater

27:43 of inhibitory cells with much more different unique number and properties capable of producing

27:50 different dialects. So action potential is language and each of these cells speaks

27:57 slightly different dialect. You want cells react to fast frequencies and process them

28:02 a very fast manner. The fastest the fastest neurons in the brain can

28:07 up to 600 action potentials a That's called 600 Hz 600 action potentials

28:17 one second. Some of the cells very, very fast. You need

28:21 because you have some very, very stimuli coming at you visual auditor and

28:25 on. Some cells are slow and function is to introduce another dimension of

28:34 . In this case slow computation and . And these rhythms that produced by

28:41 sounds, they become like an orchestra , like a symphony and an equivalent

28:48 that when you walk in the symphony the orchestra is sitting in the down

28:53 and they're all warming up and it like chaos, all the noises coming

28:59 everywhere. They're warming up. But they produce coherent tune. Then the

29:06 violence starts going, you know, timpani starts drumming in the back

29:13 you know, the cello is come the woodwind instruments so on and it

29:18 a song. Now, that song have to be uh all synchronous and

29:26 can have chaotic music too, that's , chaotic music. But from this

29:33 language of the south, the whole is going to produce a network activity

29:37 going to produce a certain frequency oscillation the network. Some of the things

29:42 going to go up and fire some the South are going to get inhibited

29:47 this kind of oscillation and the network then get communicated onto the adjacent networks

29:52 the projection parameter south. This is setup that I used to work on

30:01 a postdoc. I did my PhD Louisiana State University Medical Center in New

30:09 in the nineties and then I moved uh my first postdoc position which was

30:17 johns Hopkins University Mind Brain Institute. then my second postdoc which is this

30:24 is from the second postdoc and we it rigs here in texas and Louisiana

30:29 stand for something else. Either go on the rigs the rigs. This

30:34 a different kind of rigs. It's on the rig. It's electrophysiology

30:39 This is my second postdoc at George University which is in Fairfax Virginia about

30:45 an hour from D. C. was in 2000s and my PhD work

30:53 focused on excited and inhibitory synaptic transmission the development of the visual system.

31:01 first postdoc focused on plasticity, individual in the cortex and my second postdoc

31:10 on epilepsy and neurological disorders, abnormal activity during events like seizures. So

31:20 is a slice in there. Believe or not sitting underneath this lands and

31:25 told you that these slices are being . They're being fooled that they're still

31:28 of the brain with cerebrospinal fluid and that is being supply to them.

31:34 then you know there's only probably you 100 people, maybe 200 crazies like

31:41 . They would try to stick like or three cells at the same

31:45 Four electrodes underneath the microscope run out equipment rather 10 older. So these

31:52 electrodes that I was showing you these electrodes here. They're connected these micro

31:59 electors actually extend from this one micro extend all the way into these pre

32:07 heads we call them. And then pre amplifier head holders and holders have

32:14 manipulators, you can move things PS like nanometers or less distances. This

32:22 is floated. So anything that moves the table, anything that moves outside

32:29 table is floated, it's completely It takes about an hour to an

32:34 and a half to get an animal put an animal asleep to get animals

32:39 prepare slice and place the slice under and then once you have it

32:45 you better be sitting on that chair at least 6 to 10 hours.

32:49 that's the kind of and then you about 45 minutes of Queensland. And

32:54 semi sterile environment. So every day every night clean. These rigs are

32:59 just spotless with hot water you can't out, we can't use too much

33:03 a hot water because we have instrumentation plastics and glues that So it's a

33:10 of effort to try to get these that I was telling you about.

33:14 takes a whole day. And if were good you would get three cells

33:18 day. If you were good you get a triple patch in one

33:23 If you were amazing, you would a quadruple patch ourselves and that may

33:29 you a whole week to do And so we did it for a

33:34 and I don't think I'm gonna do anymore. But it's again very interesting

33:40 which teaches you a lot of stuff a lot of troubleshooting and problem shooting

33:46 you have to realize is that this is connected to about two stands here

33:51 are full of amplifiers, more sophisticated and current stimulators, current generators,

33:59 screens and so on neuroscience. so this is how we study

34:08 we study their activity. And now going to start talking about glia And

34:14 gonna end at 12:45 or make sure I clear out of here before the

34:19 professor comes first leo Blue and greek thought to play a supportive and insulating

34:28 for neurons. But apart from supporting insulating all the neurons are very actively

34:36 in regulating your own all transport neuronal genesis the amount of neurotransmitters that neurons

34:45 use and there's synaptic signaling and many different features. So the some type

34:55 glia that we're going to discuss. of them is micro glia microglia are

35:01 they're the smallest real elements are also most mobile real elements. They're responsible

35:08 cleanup damage, repair, scavenging, for debris. Clean up the

35:18 So, if you recall in your your class folder, you have this

35:32 class lecture documents. And you will that there are some links. Some

35:40 these links. So, I've got essay written. So now I'm gonna

35:42 you how I use Graham early to . Okay, so here's my essay

35:47 the ads and I don't that's not point. All right. What?

36:03 , let's see what we're looking at . So, first of all,

36:06 is this? It's a timescale in . What is this? It's uh

36:14 μm in space distance space bar. And what we have here are the

36:26 and all of these cells are specifically glial cells. So there is a

36:32 marker because because cells expressed our specific , we can also tag them.

36:38 we labeled all microbial cells. Scientists wanted to go do something someplace not

36:46 . Uh and there is an Boom right here in the middle and

36:54 you're seeing, what you're seeing within . We finished within minutes following the

37:04 . What does marco glial cells due start extending their processes that we

37:11 So the other parts of the body have like activated activation of macrophages in

37:16 brain is microbial cells is injury, inflammation. Microbial cells get activated,

37:23 become mobile that starts seek out the they also involved in. The cytokine

37:30 the pro inflammatory cytokine regulation. And essentially your neuro immune neuro uh inflammatory

37:40 that you would see. And michael salsa involved in in in these processes

37:46 the most mobile elements. And besides their processes, he actually over time

37:52 , you can see that selma's also over certain periods of hours of

38:00 It's not only the processes that extend so must actually move through the brain

38:07 into the location where they're being called . This is micro glial cells.

38:17 cells that will talk in greater detail we'll come back and talk to them

38:21 . As astrocytes and the astra sites involved in. We call them originally

38:28 chores. But now we know that involved in regulating the amount of

38:33 So they regulate the amount of neurotransmitter is available to neurons. They're involved

38:39 regulation of synaptic plasticity and synaptic communication they are responsible for regulating the local

38:47 . So make sure that there isn't much of the neurotransmitters or too many

38:50 the ions of a specific kind that risen and astrocytes will be able to

38:56 this abnormal chemical changes locally during early . Our neurons are not born

39:07 But rather they're born in specific parts the brain and from those specific parts

39:13 the brain. They migrate. That that visual neuron that is in the

39:18 visual cortex, in the occipital lobe . It's not born here. It

39:25 him. It's born in specific areas the brain. We won't be discussing

39:31 that are more internal. And from areas of the brain my migration starts

39:37 neurons will migrate until they find the destination until they find their cortex there

39:45 , right their city and they find neighborhood which is their circuit and then

39:50 find their mailbox which is them. that's that neuron that found its mailbox

39:57 the area. And to do this and process outgrowth for neurons. You

40:04 the other type of cells. And are radial glial cells. And what

40:13 shown here is something super interesting. is a neuron and this is a

40:21 glial cell and this neuron now hugs glial cells. It becomes membrane and

40:31 plasma continues with the cell. The infuses and then uses it as a

40:40 this membrane to move and migrate that thoughts. So you'll have radio glee

40:51 . Oops. I don't know what is. I don't know what that

40:57 . Uh you have radio real cells they ate in this migration. This

41:03 another example of neuronal migration. In case it's without radio real cells.

41:11 can see that there's a lot of going on. A lot of touching

41:16 on, fusions, separations and movements different directions as the neurons are migrating

41:24 they're using in many cases radial glia their guide sort of as a

41:29 The latter as a ladder to climb to layer two in the cortex to

41:35 off to layer forms stay there and glial cells can also become neurons

41:42 So they're almost like a multi pluripotent . So growth factor release uh glial

41:55 can release neurotrophic factors that influence slower . And in general if you're thinking

42:06 is this your cup? I was wondering if anyone found my welcome to

42:15 and look. So uh growth back released like neurotrophic factors also can influence

42:23 slow growth factor at least like slow . Uh And uh in general when

42:33 thinking about neurons, neurons produce action and glia do not produce action

42:41 Glia communicate with much slower calcium waves they're active. They have membrane potentials

42:50 they do not produce these fast action that neurons do. And now you

42:55 envision that you almost have two different scales. You have fast action potentials

43:04 neurons fast neural transmission and communication between and then you have this other temporal

43:11 which is slower which is in minutes micro glia which is dealing with inflammation

43:19 is dealing with metabolism and production of and you have these temporal scales operating

43:27 the same time. Very fast neuron neurons, slower glee are taking care

43:33 stuff too And so there are different but very important roles in the brain

43:41 general glia control formation of new synapse number migration of neurons and synaptic

43:51 . Also so many different functions can ascribed to clear. For Myelin Nation

43:57 have Myelin Nation in the P. . S. Peripheral nervous system.

44:01 have Myelin Nation and the C. . S. And this is you

44:05 actually there is a difference between the to peripheral nerves right and nerves in

44:10 hands and and your legs that you regain. You can regain feeling in

44:16 nerves. These nerves can partly repair depending on the damage the physical damage

44:21 the nerve or some other disease like C. N. S. Will

44:28 regenerate. The nerves will not It's a different chemical environment, it's

44:34 different installation and P. M. . Each one of the nodes of

44:39 which comprises the smiling nation of the . Each one of the nodes of

44:45 is a single swan saul with nucleus is wrapping around to form a single

44:52 in the C. M. You have other types of cells illegal

44:56 side so there's illegal Denver sides instead one salad forming one segment, one

45:03 of illegal Denver side is going to out. That's going to do this

45:08 of a weird wrapping around from the to form that myelin segment in between

45:15 segments. You have nodes of wrong and in those of Ron beer.

45:20 action potential that gets produced at the initial segment. This action potential will

45:26 regenerated each note of Ron beer so when it reaches its external terminal it's

45:33 same amplitude and the same dynamics as was from its origination point.

45:41 so my elimination here and you'll see sheets wrapping around nodes of reindeer.

45:48 have mitochondria and you'll have energy You'll also have a lot of both

45:53 sodium and potassium channels. That's what action action potential. And this is

45:59 regenerates action potential at each note of . And so you will know

46:03 A lot more about that too. had a very interesting question yesterday.

46:09 do cells know when to stop the segment? Uh and maybe you'll get

46:17 of the clues and some of the in the subsequent slides. But you

46:22 pick up there's a finite size for process. In other words, this

46:27 from a legal tender side cannot be one yard wide or one micro meter

46:35 . It's gonna be about one to micrometers wide. So daniel read

46:43 you have the limitation in size. does it precisely know that? It

46:49 to stop at the note of wrong . We don't don't exactly know that

46:54 there is selling silver recognition. There protein protein interactions that we guide these

47:00 . Uh And we'll talk about some these and in particular we'll talk about

47:07 with respect to myelin compaction diseases and elimination diseases. So it turns out

47:15 this compaction is wrapping around is mediated at least seven related podiums which are

47:23 this. This this myelin compaction. or myelin associated glycoprotein is one example

47:32 the seven proteins. And Maggie is for initiation of Myelin Nation. That

47:37 that you have proteins that are responsible initiation proteins. Um South south and

47:44 protein interactions are responsible for wrapping and there are those that are responsible for

47:51 . In addition the level of the of the proteins is very important.

47:58 what happens in in some of the Myelin Nation diseases and what I have

48:05 is Encephalomyelitis. Written on top We already know Encephalitis is an infection

48:12 inflammation of the brain. Encephalomyelitis is condition that that infection and inflammation in

48:19 brain can actually cause de milo And there are models. Animal models

48:26 so we can recreate this D Myelin with viral infections. But we also

48:34 to model not just Encephalomyelitis which is real thing. People get encephalitis.

48:39 you heard of Syphilitic ticks? You not be from one of those states

48:45 ticks are rampant. My cousin had twice in the last three years because

48:52 stays in the countryside by the lake ticks of breeding every spring and he

48:57 bit like five or six times and ended up in a coma in the

49:02 with encephalitis. So we all know most dangerous animals in the world are

49:10 bugs, little mosquitoes. Little ticks carry all of these diseases. You

49:16 . So but so so you want replicate and you can do that.

49:19 can infect the animal, You can the virus into animals. You can

49:25 the neuro degeneration and do my elimination and you can observe the symptomology of

49:31 . Perhaps one of the most uh diseases of demonic nation and the

49:37 N. S. It's multiple It's here in yellow multiple sclerosis.

49:44 multiple sclerosis can be linked to chromosome mutations. You have to have recessive

49:52 to that Palios. And one of symptoms of multiple sclerosis disease is is

50:00 and sometimes convulsions. Okay so that's is multiple sclerosis. Demon eliminating

50:07 But is multiple sclerosis autoimmune disorder Your body starts looking at myelin as a

50:16 invader and starts destroying its own auto immune disorder, developmental onset and

50:27 . See onset typically in the 30s up why? Great question. All

50:35 and now you can have a disposition cancer. Alzheimer's never forming outside triggers

50:42 mutations. Second Aliyah mutated. Why that have genetic predispositions are likely to

50:53 diseases and why some are no I know in science. You want to

50:59 at a human condition like this and want to try to replicate as much

51:04 the human condition in an animal So when people tell these an animal

51:09 , not because you're just taking around doing something, you're gonna have a

51:16 . You're gonna create a genetic mutation the animal. And you can create

51:20 that are called transgenic animals. That you have a mutation in a specific

51:28 and you can have formation uh the nation, okay. And this animal

51:36 a shiver animal. So it will tremors and convulsions that you would see

51:42 M. S. So a Mass demolish nation can take place in many

51:47 parts of the brain. You already that certain parts of the brain are

51:51 for executive function. Other parts of brain responsible personality traits, memory,

51:57 , where that'd amalgamation happens will affect particular function. If it is affecting

52:04 cortex, motor pathways, speech you will have problems with those particular

52:13 . So when you're doing a you're doing a genetic model, you

52:19 to replicate what's in the genes. doing a cellular model. Because you

52:26 a mile the nation, you're doing behavioral of symptomatic observation on these

52:32 Yes, they have tremors, they seizures. You're trying to replicate and

52:37 as much of a human condition in animal as possible because that allows you

52:45 to say whether you have a good or a bad model if you inject

52:50 virus into the brain and you caused , that's not a good model for

52:56 mess necessarily. But it's a great for viral infection and inflammation driven desalination

53:04 this. I'll get to your question this final image here. This animal

53:10 transected with normal gene. So it's gene transfer action sort of, you

53:16 think of the future gene therapies in way and there's a partial restoration of

53:22 of the myelin. So the gene important, whatever gene is producing is

53:28 protein that that that helps preserve the and that stops the attacks and all

53:34 immune response or something like that. all very important. Yes.

53:43 so it's a different circuit. it's a it's a different disease.

53:51 your question is very good because I mentioned to you that certain symptoms and

53:59 will be overlapping between diseases. in Parkinson's, you have what are

54:05 typical Parkinson IAN bombers, the pathology the disease is that from the neural

54:13 that are involved is different. It's larger diseases, dopamine impairment.

54:22 and sometimes parking Sony and tremors can into an iconic seizures, even a

54:30 and that symptom you would observe in types of epilepsy is also, and

54:34 why I say that there's overlap between . But you're correct for Sony in

54:39 , but also if you created an model of Parkinson's, you would be

54:44 a different part of the brain targeting dopamine ergic circuit. Using a different

54:49 for Parkinson's. There's actually a very chemical model too. And will allude

54:55 that. I think in this course not sure if I talk about in

54:57 course or cellular neuroscience. Very And then in the periphery you have

55:06 type of myelin dysfunction of the myelin . And that's shark lot narrative museums

55:13 it's a developmental disease. So that it happens during early development. It's

55:21 chromosome 17. You have a duplication chromosome 6 17. In this case

55:27 have a over expression of this N. P. Two, two

55:35 people that have uh this mutation they in the periphery partial loss of

55:43 Now, if your peripheral nerves are signaling correctly to your lower limbs from

55:49 spinal cord, not sending the correct during the development, that means there

55:54 no proper contraction of the muscles as muscles shape themselves and the bones grow

56:01 the development. A lot of people have deformities in their lower limbs.

56:06 will have problems with walking and with and you can see that's mostly affecting

56:11 lower limbs. There's no cure for disease. You can detect it as

56:18 as possible and place people into the braces and physical therapy so helps them

56:26 their bones and their gay as a of the development, obviously it depends

56:31 world you live in and what medical you have around you and diagnostics.

56:36 know, if you're somewhere in the of nowhere, 10 hours away,

56:41 surrounded by the desert or by the , you know, this is something

56:47 you may not understand or the families understand this condition early on, you

56:52 not see it. And I think kid is working, walking funny or

56:56 like that. So it all very depends these are two more diseases that

57:02 adding actually three because encephalomyelitis, but the perspective of a human disease you

57:09 have and so for myelitis, but sclerosis is important to take notes and

57:17 cut marinated disease. And finally this puts into a great perspective the cells

57:23 we're talking about the good emphasize astra and you can see that astra size

57:29 be controlling synopsis and Sinatra genesis, transmission and also have their end feet

57:35 the micro capillaries forming part of the brain barrier have the micro glial

57:41 They have these dependable cells that are surplus final fluids from interstitial fluids.

57:47 dependable cells are potentially potent also can other types of wheel and their own

57:54 and the last slide in this lecture on blood brain barrier and I don't

58:00 to just do it in one But I want to remind you that

58:04 brain barrier is a good thing because in your blood doesn't always cross freely

58:08 your brain and you don't want that when you drink a big Assume

58:13 you don't want all of these all of the things you consume going

58:17 your bloodstream, going into your brain the end to feel yourselves will form

58:22 junctions, parasites will surround them, , surrounding all of these checkpoints.

58:29 the substances crossing into the brain. we talked about how during COVID-19 you

58:34 inflammation and breaches in the blood brain and now the viruses and other molecules

58:39 pass into the brain much easier. the most part this is a really

58:45 protective barrier and the things that get the brain that have to be

58:49 Maybe they have to have transporters that them across. Maybe they're like facility

58:54 means that remembering soluble and the cross through these membranes into the brain.

59:00 the same time. When you think neurological drugs and I'll leave you with

59:05 stock for for the labor day most of the pain killers uh medicines

59:13 we consume, we ingest. And we ingest 200 mg of ibuprofen,

59:19 doesn't mean 200 mg of ibuprofen and helping us with a headache, a

59:24 of it is gonna get into the and then a fraction of it is

59:28 cross through the blood brain barrier. with some drugs it's a problem.

59:33 you will see commercials that somebody's trying treat their migraine. But then the

59:39 will list are you having suicidal Are you having diarrhea? Are you

59:43 over and and as you seem bleeding your abdomen, all of these

59:49 Why? Because in order to affect brain condition neurological condition effectively, sometimes

59:55 drug does this are quite high that swallow and they cause the side effects

60:01 the systemic effects that people can experience and another stuff like that. So

60:08 we come back on a week from , on thursday, so again,

60:14 have Tuesday off and I urge you review all of the material on

60:18 It's a good halfway point. When come back, I will tell you

60:23 how would you want to design a pharmacological drug? What are some of

60:28 features that you're gonna have to think for that drug to be effective for

60:32 drug to effectively across the blood brain . And maybe maybe even dream of

60:39 a drug that will be self One of those 21 setbacks of

60:47 Think of a way you would target drug to one of those 21 subtypes

60:52 . How would you go about Okay, thank you very much.

60:55 I will see you all next thursday on zoom. I'm gonna exit

61:06 I save the lecture. Please email guys if you have

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