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00:03 This is Lecture five of neuroscience and have just having a great discussion here

00:09 class that for those of you that just watching the videos you missed out

00:16 it. And if you're just watching videos, we're almost halfway through,

00:22 be more than halfway through the first of the course is this is a

00:27 to face course. You should be the lectures taking notes and reviewing videos

00:40 as a supplementary material. So, is only the next term. It's

00:46 the primary source of learning and I encourage you to take a lot

00:51 questions in class and advantage of sitting classes that you hear all of the

00:57 . Uh, if I don't repeat on the video, advantage of sitting

01:03 classes, seeing everything that I write uh wide board, which does not

01:10 unfortunately as well on the videos. so that's basically my message that if

01:19 want to do well, you should on the material that we discuss in

01:24 lectures. Of course, definitely the is you should use your book.

01:30 there's some information in the book that in greater detail than what we discussed

01:34 the course. There's some information in course that we discuss in greater detail

01:40 it is discussed in the book, my questions on the exam will be

01:46 accordingly to how much time we spend the materials during the lectures and not

01:53 what is in the book. okay, so make sure that you're

02:00 yourselves that you're attending and learning all the material. if you want to

02:05 yourselves where you left off last time we had lecture for and we finish

02:12 lecture by talking about neuronal networks and about how different cell subtypes are different

02:22 different parts of the brain. And spent quite a bit of time on

02:26 diagram and there is a class supporting documents that has a paper in it

02:32 hippocampal circuit inhibitory neurons in your folder the blackboard that you can review and

02:41 the figure legends. But I will you what I would like for you

02:46 know about this diagram on the but this is where we ended up

02:50 time. So this is it here this is what is labeled as lecture

02:59 . And today we're gonna go through and then we're gonna go into lecture

03:05 , kind of a word ends here pick up with glia. So we'll

03:09 glia and then we'll cover the simple arts in the south and the south

03:16 within the outside of the spinal So when we talked about this

03:26 we talked about structure called McDonough uh . Oh, hippopotamus campus.

03:54 is that gonna make it help you it? Hippocampus. Okay, so

03:59 is the things that I would like you to know about the slide came

04:05 campus. What did we say about for campus? It is our key

04:09 which means it is predominantly three layer . So Arky cortex and archy park

04:17 for archaic. So ancient cortex. hippocampus and this this particular section we're

04:29 at is only a portion of the . So this is a circuit within

04:34 hippocampus that we're setting on the And if we were to stay in

04:40 of the cells with glutamate in the , so all of the cells that

04:47 be expressing and releasing glutamate, Which excitatory cells, we will realize that

04:58 of all of the neurons in the in this area that we're looking at

05:05 excited to glutamate sounds. So we can repeat the same question what is

05:13 proportion or the ratio of the inhibitory , inhibitory cells in hippocampus that release

05:21 as the major inhibitory neurotransmitter in the Gaba will account approximately the other 10

05:32 20% of neuron. Oh, so so now what is the big difference

05:43 the excitatory cells and the inhibitory cells the circuits that we're discussing. We're

05:49 about the fact that the excitatory cells are parameter cells, they can talk

05:55 each other within local circuits but there are excitatory projection cells. Therefore they're

06:03 project into the adjacent circuits that will contain sad story and also inhibitory

06:11 Now, inhibitory cells can also talk each other and they can talk to

06:19 excitatory cells and inhibitory cells gather releasing but their local network into neurons and

06:30 cells do not have projections that come of the networks, but the excitatory

06:38 have the projections that come out of networks. The reason why I'm explaining

06:47 circuit to you is because this circuit what we call a canonical circuit,

06:53 means that we will find similar type arrangements. The ratio of excitatory versus

07:01 cells. Right? And also the that the diversity here is the cellular

07:09 population starts from the diversity and the cells in particular. So this is

07:16 going to be a theme in the cortex or neocortex, which is a

07:22 cortex, which is a six layer . Now, some of the important

07:29 that we talked about when we looked the slide is that we can distinguish

07:35 cell subtypes using a variety of different and the take home message is that

07:41 modern day neuroscience we have to use techniques in order to actually prove the

07:51 , prove ourselves, prove our audiences we are studying a particular subtype of

07:59 . It's not so difficult with excitatory in the hippocampus or even in the

08:05 . Because excited to the parameter which will projection cells and they'll project

08:11 axons out of this hippocampal network. , these excitatory production cells are very

08:20 to each other morphological e essentially We also started talking about the dialects

08:29 neurons in the sense of the patterns action potentials they can produce. So

08:33 particular parameter all cells will also produce patterns of action potential, so identical

08:42 . It's also indistinguishable and the only that can definitively determine the difference between

08:49 different cell types are some inter cellular specific markers that are present in certain

08:56 of parameter self C. B. and others are C. B.

09:02 because essentially expression of molecules expression of binding proteins or other enzymes and such

09:11 the cell also indicates a different function that cell. Even if it cannot

09:16 observed outwardly through morphology or even inwardly their dialect they're speaking, they may

09:24 be different subtypes of cells even if speak the same dialect. That's what

09:29 getting at. Now when we look the inhibitory cells that we said that

09:37 about 21 different subtypes of inhibitory cells destruction. The Hippocampus inhibitory cells can

09:44 discerned one from another based on the based on their cellular location. But

09:50 the end, the fact of the is that some of these inhibitory cells

09:55 have the same dendritic morphology and the and these yellow cups that you remember

10:02 are the synaptic contacts and the locations the synaptic contacts with the respect of

10:07 Samata access to the programmable cells. these axons from number to number four

10:16 target the same regions of the parameter cells again to distinguish between them.

10:22 would need to use cell specific markers would distinguish these two different subtypes itself

10:32 another thing that we talked about hippocampus we mentioned is that hippocampus is very

10:40 for semantic memory. Okay, learning memory. So if you're memorizing

10:48 you're learning something, if you're learning facts, the faces, the

10:52 the stories of when Luigi Galvani, used the laden jar to stimulate the

10:58 leg. You're learning this through hippocampal to do these circuits that you're looking

11:06 . And so it's really the major of semantic memory or it's also involved

11:12 emotional response and emotional information processing. inevitably a lot of the memories,

11:21 sharp memories that we have retained and with us for a long time or

11:27 have to do with a heightened emotional rather than just block things happening around

11:34 . So these inhibitory cells then they the excitatory projection cells locally within the

11:45 Because of the variety of the inhibitory . You have a variety of dialects

11:51 can be recorded in this case, looking at the neocortex. This is

11:57 layered structure Neocortex and the parameter sounds be producing this type of dialect

12:05 but other cells with the same input actually produce very different frequencies and very

12:13 patterns continues versus bursting patterns versus certain , very different patterns of action potential

12:24 , action potential in the end results the release of the neurotransmitters. So

12:29 frequencies and the patterns, electrical patterns result in different frequencies and patterns and

12:37 release of the neurotransmitters in the Yes. What accounts for the difference

12:44 the territory in why is that why that the case? Because it is

12:58 just in these specific circuits like in Hippocampus and Neocortex, you would see

13:04 dominated number of cells and in particular certain layers, 80, parameter cells

13:12 the much lesser numbers inhibitory cells. the parameter cells are pretty much the

13:18 Ortho logically and functionally and the inhibitory are very different. Now there are

13:24 in the brain and nuclei in the that will not have any excited to

13:28 . So when we study, for , following us in the brain which

13:33 all of the sensory and information. has different nuclei and some of these

13:42 will have the ratios and the proportions excitatory cells to inhibitory cells in the

13:47 way. And then you learn about other nucleus called the particular formation and

13:52 polymers that is all inhibitory. So , canonical in the sense that you

13:58 see this ratio proportion why it is a way if you think about

14:05 the diversity and communication, it comes the inhibitory self. So that's the

14:11 that I can sometimes use an analogy if you uh have a switch on

14:21 is excited to herself and the light comes on. It's pretty boring.

14:27 want to have the dimmer function. want to be able to turn them

14:31 and on as fast as you want and that's what the diversity of these

14:36 cells provides. And later as we'll about other neurotransmitters apart from glutamate gaba

14:44 today we'll learn about slicing but we'll about a mean neurotransmitters that are located

14:50 very specific areas of the brain. will be adding color to the light

14:55 . So it's in a way that then then uh there's certain networks that

15:02 to encode the information that they will in a very robust way and maybe

15:08 why they excited to ourselves. so dominant, especially in the interconnected

15:13 that need to be engaged in order perform a given task. Yes,

15:27 meant that you will find these arrangements of the cells and certain types of

15:34 in which these cells communicate on their and with each other in different parts

15:38 the brain. I have a question with this with this, Not

15:45 but uh, I just, I know if it's a question but since

15:49 conferences related. So one of the functions like that is important in learning

15:54 memory for that. It's not that or that long term pronunciation.

16:02 forgetting that will be like needed. have a high number of for which

16:09 so okay, so, so what , what, what you're mentioning is

16:19 cellular process called long term potential And this cellular process is like a

16:25 substrate for learning and memory. So will get into that a little bit

16:32 into potentially ation. But it is to what we already talked about is

16:36 plasticity. And in order to encode new information in order to learn

16:42 It's not necessarily that only hippocampus has potential patient and you only need to

16:47 locally in another potential chemicals only in is for any of the new connections

16:53 be strengthened. They have to be ated. They have to be made

16:59 . And there's a number of chemicals are involved and there is chemicals are

17:03 to be different. Different parts of brain. Sometimes they're reliant on

17:07 sometimes reliant on dopamine and different rules different encoding information will rely different chemical

17:15 . So uh it's it's it's it's little bit complicated. But you're you're

17:23 thinking is uh and the question is silly. It's actually maybe advance for

17:30 we are at the moment in the . But we'll touch on these things

17:35 later in the course, we'll talk plasticity, potentially a shin at the

17:41 to describe to you the plasticity is ability for the cells to form new

17:45 , strengthening connections lose those connections when say L. T. P.

17:49 potentially ation. You also know that L. T. D. Which

17:53 depression which means you have to get of the synopsis. So as you're

17:58 new information you're potentially shedding all information different times of the year, different

18:05 and different decades of your life. may prioritize certain types of learning and

18:09 types of information at an expense of things because we have in the end

18:18 adults finite number of synapses. And despite the variety of the cells will

18:24 have only 150, sub tasks which be even more different ways of processing

18:34 . So uh yeah we always have think about that. That potential

18:41 strengthening, building this synopsis also comes an expense potentially weakening, shedding old

18:47 once as well. So but we'll back to some of these topics later

18:53 the course. Uh Sure. So people do these kinds of recordings,

19:01 they try to record from neurons and can try to record from individual

19:07 So we can if you recall we visualize neurons and we can visualize neurons

19:12 infrared microscopy. And the neuron on left and you're on the on the

19:17 . This is a cross diameter about micrometers diameter of this pie path path

19:24 about one micro meter too. And these cells receive identical input but they

19:31 a completely different output in the patterns their action potentials to sell on the

19:36 is very fast frequency of firing the on the right is slow and in

19:41 when we look at the diversity of dynamic range, how fast or how

19:48 neurons can fire. Some neurons will fire maximum up to 57 herds which

19:55 5 to 7 spikes a second. so fast. And then on the

19:59 range we have neurons that will produce of 600 hertz of 600 spikes the

20:06 . And that's because our sensory stimuli at different frequencies for us to create

20:12 unique thoughts paintings writing in our Motor output requires different frequencies slow and

20:21 but these neurons will receive identical They'll have very different output during these

20:28 which are called whole cell or patch recordings. The pipettes can also contain

20:33 . So in this case it contains dye called neurobiology and the bios

20:38 After the experiment you can reconstruct the of these cells that you reported

20:44 You're not using Golgi stain because in stain is 1 to 3% of non

20:50 neurons that are going to pick up stain and reveal the morphology using your

20:55 . And then histology so that you inject dye and sells your reporting from

21:01 reconstruct them more ecologically. So when alcohol was doing cellular reconstructions using camera

21:09 . This microscope with the armed and to reconstruct the neurons. This is

21:16 day done with the neural lucida software with a pretty intensive and engaged human

21:25 of that software. So it cannot be an automated reconstruction of the south

21:30 still a human element involved. And after you do the recording so you

21:35 the electrical activity. You know what cells look like. You know their

21:40 , you know their morphology precisely. see some of the parameter cell and

21:45 action going out. This is actually out to be number seven cell which

21:53 oriented molecular. I don't get Orients layer all the way to look

21:59 the molecular larry because it has these axons that go all the way

22:04 And then finally to convince the reviewers had to cross stain it or the

22:10 marker histology for Samantha status of these are positive for Samantha status. And

22:16 then reviewers said, okay, your is not good enough and that wasn't

22:20 this was not the point of the . This was the point of the

22:26 and these multiple recordings. But people enough like me for years sitting under

22:32 microscope to do these brain slice recordings operation. It takes about an hour

22:38 a half to two hours in the . Then you have to have a

22:42 bit of coffee with the slices recover then you go for it. So

22:47 10 30 11 and it's like sort growing into a submarine and you may

22:54 somebody distracts you for lunch like around 32 PM. Or maybe you don't

23:00 that the sunset since already six PM you're still poking and stabbing cells under

23:06 microscope. So but the reason why want to do these multiple recordings is

23:12 the reason why you would want to all of these techniques is not just

23:16 say I recorded from this subtype of . I already knew I was targeting

23:21 number seven And parameter all cells. that was nothing new. This was

23:27 in 2000. Mm I want to maybe nine or something like that.

23:35 paper. This is my research But that wasn't the point. I

23:41 there to do all of the immunity the chemistry, electrophysiology reconstruction of cell

23:49 . Just to say God, Cell seven, just like five. Guys

23:52 me already showed the morphology. We answering a different question and we were

23:59 multiple cells at the same time. question was which cells are responsible for

24:07 epileptic seizures? Is it excited to ? Is it inhibitory cells? Which

24:15 of the cell? Is it number or is it number two?

24:20 How is it connected to each How do they talk to each other

24:24 normal environment? How do they talk each other when the brains become a

24:31 optic? Like? Okay, so was the question. So we would

24:35 multiple cells and we have to describe for the reviewers. We have to

24:40 through all of these techniques to prove we recorded from cell number 74 10

24:46 . It'll sell to prove. But wasn't again just to do that.

24:50 was to show which cells were And we discovered the inhibitory cells would

24:57 more active at first and synchronizing seizures certain types of seizures. And what

25:03 discovered in the slices in the And we took three years to prove

25:09 the reviewers two years later was found humans, similar patterns of activity.

25:18 the fact that in epilepsy and humans cells synchronized first to start the

25:27 So that was really rewarding because that my postdoc work and you always want

25:32 do whatever you're digging around on the or and tested or in a Petri

25:37 eventually want to know that you're contributing you're relating to something that is happening

25:43 humans or that maybe it's going to applicable uh service for cure for for

25:53 some disease that you are interested So these are pretty sophisticated recordings managed

26:00 do multiple at the same time. was my rig, we call it

26:05 in texas rig can be different if in oil, there's oil rigs and

26:10 fishing this fishing rigs and if you're electrophysiology there, electrophysiology rigs and so

26:18 sophisticated. This was George Mason University I did my second postdoc and we

26:24 interested in Apple, etc. And different cell subtypes contribute to initiating seizure

26:33 sometimes we'd run out of equipment. you know this this is a pen

26:38 then using it as a holder because other more expensive holder broke and I

26:43 in the on the role, so speak. So I had to replace

26:47 with just depend and continued the experiments took a picture of that. I

26:50 it was pretty fun. Anyways, concludes our discussion on neurons. You

26:57 a lot to learn about different sometimes neurons, you're going to still learn

27:02 about neurons at the very end of lecture. But right now we're gonna

27:06 into now when we talk about Glee the very beginning of this neurons and

27:18 collection of I had difficult race at very beginning I said that Glia Again

27:32 about 90 of the cell populations in brain and neurons comprised about 10%.

27:45 I said neurons are like chocolate chocolate in the cookie and glee is like

27:50 dough. In reality you cannot have normally functioning brain without having the dough

27:56 the chocolate chips. So, and lot of science because neurons produce action

28:04 and you don't, we have communicated slower waves through calcium. So neurons

28:13 the fast ones, neurons can fire hertz a second, we communicate within

28:18 of milliseconds to seconds. So we two different temporal scales of processing neurons

28:27 uh few hurts a second to hundreds hertz a second and glia two

28:34 Essential. Okay, glia for a time we thought to serve a support

28:40 insulation function and that meant that they not may be looked at as importantly

28:50 neurons and so that is not the . Glia is very actively involved in

28:59 different functions in the brain. From development to control of blood brain barrier

29:06 control the formation of the synopsis to of plasticity and aging. In the

29:12 , we is very intricately involved in . So today we're gonna learn about

29:18 types of glia and we're going to primarily on these types of glia microglia

29:26 of legal Diandra sides. And also is not shown here that is prevalent

29:31 early development is radial glial cells. micro glial cells are the smallest and

29:37 most mobile units in the brain that involved in scavenging and repair following the

29:43 . And also that immuno inflammatory They control the release of cytokines in

29:50 brain. So when you talk about 19, for example, even on

29:55 radio, you turn on NPR people talking about cytokine storms in the middle

30:01 the crisis with covid 19 and cytokines a normal process of evolving inflammation and

30:09 response to that inflammation in the body the brain. However, it is

30:14 , It is off balance. It also be detrimental and causing abnormal pathology

30:20 the brain. Now astra sides are intricately involved in the control of what's

30:26 at the synapses. So they're involved the synapse formation and synaptic genesis.

30:31 involved in neural transmission or communication between and a lot of funds they viewed

30:39 as a third part of the synapse synapse where two neurons are communicating with

30:45 other and astra acidic cells are actually in this communication. There are also

30:53 . The glial cells are involved and the amount of the excitatory glutamate neurotransmitter

31:00 the brain. So they in a control the amount of excitation that is

31:06 for neurons. The amount of excitatory that is available for neurons to communicate

31:14 . They're also having their end feet the capillaries here becoming a part of

31:21 we call the blood brain barrier. we'll discuss that in a few slides

31:25 well. Ah Legal tender sides in central nervous system are responsible for forming

31:32 violent segments and insulation of the Recall that axons are insulated, not

31:40 rights nor are the selma's and the are specifically insulated using illegal dendrites sides

31:48 the C. N. S. you will see that in the

31:51 M. S. It's a different of cell that is called Schwann cell

31:56 at that in the second. Then have a pen dermal cells here that

32:00 separating the spinal ventricular spaces from the spaces here in dependable cells are thought

32:07 be potent, which means that the may become other types of glial cells

32:18 developed into the other cells listed here for a lot of the information that

32:28 discussing. For example, there is supporting lecture materials. And if you

32:33 to that folder there these videos and some of these videos lead you to

32:40 videos with some commercials that are not for But the content of the videos

32:46 I wanted to pay attention to not advertisement for commercial. And what you

32:51 see in this video is this dock represents an injury and all of the

32:58 and processes here are micro glial So the staying here specifically stains microbial

33:07 in their processes. And what is evident here is this is a temporal

33:13 in minutes. This is 10 micrometers space. That's the scales. You're

33:18 at. What is very evident is following the injury, you immediately see

33:27 the processes of the micro glial cells extending themselves physically. Talk about the

33:34 of the injury and that is happening 15 minutes. So, minutes following

33:42 injury. And then at some point actually with this time lapse what you're

33:49 is the soma of these cells that located further away now are migrating in

33:58 the side of the injury. that's where they're going to help with

34:03 inflammatory immune response repair and damage to brain tissue. Okay. And they're

34:11 most mobile elements out of all of cellular subtypes the most mobile, they

34:19 move through brain tissue from the surrounding in this case forward the side of

34:25 injury. And that injury could be physical traumatic brain injury. That injury

34:31 be a rupture of the blood that maybe stroke. That injury could

34:38 infection affecting more of a specific area the brain over the other areas.

34:45 this is the micro glial cells and video shows the micro glial cell function

34:54 well. You can see that within this side of the injury is engulfed

35:01 the micro glial cells that have migrated so much and processes to it.

35:08 this is a during early development you another type of self called radial glial

35:16 . And these radio glial cells are arms. They're like lattices for neurons

35:24 travel along when during early development the circuits are forming in the brain

35:33 assembling itself into different nuclear hippocampus and cortex. There's only a few areas

35:40 the brain. When neurons are That means that that neuron that processes

35:47 information and the back in the occipital and the primary visual cortex. It

35:52 not born there. It was born very specific internal areas of the brain

35:59 we don't really talk about the birth migration or the migration of neurons but

36:03 migrate to their final destinations. So neuron that was born. Sub cortical

36:09 going to migrate into cortex is going migrate into the occipital cortex and it's

36:17 find this location maybe in layer And that is gonna be its final

36:22 destination within the network. So to that migration they will use radio real

36:29 and there's actually a cytoplasmic continuity that and this primordial tissue to clean these

36:37 . One of them which essentially is the other one to climb belong to

36:43 its destination. So this is the that is happening during early development.

36:51 then when I said when you're born happens is that you have everything connected

36:55 everything you have a lot of synopsis then personally you're going through this refinement

37:00 connectivity and development of specific talents and and such. So now this is

37:10 the party going on over here. migration party. Yeah. And this

37:19 what's happening in the in the early brains that one can observe And again

37:25 will find these in your supporting Lecture documents these links to the different

37:32 and I can see that maybe some them are hidden from you right

37:37 So I'll make sure that I will these as an additional resources you can

37:41 for themselves. Some of them will figure legends as well. So I

37:47 activate this for you to view and you will find these in the supporting

37:51 lecture documents. All right so radial cells. Glial are also involved in

37:59 factor release growth slow growth factor released control of that. And astrocytes are

38:06 in blood brain barrier so but no potentials. But rather calcium waves.

38:13 for the mile information in the N. S. You have a

38:18 Denver sites and illegal denver sites in C. N. S. One

38:24 of one arm of the cell will a single myelin segment on the axons

38:30 neurons. That means that a single tender side with its multiple processes can

38:37 multiple segments on different neurons that are the vicinity of this illegal deandra

38:44 Okay so there's a cell to cell that happens. And then once the

38:50 says okay you're a legal tender side we can dance together. Then the

38:55 tender side starts wrapping around that accident the periphery and the periphery. Again

39:02 is peripheral nervous system, everything outside spinal cord, everything in your

39:08 All the nerve endings coming out of brain stem that's outside the CMS proper

39:14 the periphery. You will have my by Schwann cells And in this case

39:20 single Schwann cell is a single axon in my eliminating that peripheral neuron.

39:33 this is a cross section through it astrocytes. Still most of the space

39:40 the brain that is not occupied by and blood vessels. So you can

39:44 how much of a of a massive exercise. No decides if you were

39:51 make a cross section in this case optic nerve fibers that are coming out

39:55 the retina. You will see again my inclination is really compaction of the

40:02 and then wrapping of the smiling around the proper installation of the excellence.

40:09 in between each one of these myelin you have a note of run

40:15 A note of run dear functionally will action potentials and will contain high levels

40:21 what is to come in the next lectures, voltage, gated sodium and

40:25 educated potassium channels to reproduce this action . So the point being is that

40:32 amplitude of the action potential that gets here at the axon initial segment by

40:36 selma. It's the same as when arrives at the each note of run

40:42 and as it reaches its final terminal final destination. So very important for

40:52 communication. Right? What happens if lose insulation around wires? It's called

40:59 circuit things start burning up and light start burning up and stuff like

41:05 Right? So now inst installation is important for precise current conduction and which

41:16 precise communication between cells or between cells muscles. So this slide actually talks

41:27 some of the diseases that we started as they relate to Myelin specifically here

41:35 the condition that is known as D Nation. So, for this myelin

41:40 form there's a number of proteins myelin proteins that are involved in this process

41:46 the myelin compaction and the proper formation take place. There's about seven related

41:57 . Examples of such proteins is like associated glycoprotein, which is important for

42:04 to cell recognition and initiation of myelin . That means that there are other

42:09 that will be involved in compaction and of how much of it gets

42:15 So it's a complex network of proteins is involved in regulating the normal Violin

42:23 and compaction of Myelin around the Uh this is an example where you

42:31 full mile Island nation here And in case this is an animal model of

42:39 we call a shiver mutant in this model is created via genetic mutation particular

42:48 18. That leads to the myelin and that leads to shivering to traumas

42:57 convulsions and the reason why we're talking this animal model here is this animal

43:04 is a model of multiple sclerosis. , this is another neurological disorder.

43:10 you can add on to your list disorders. We've already discussed Alzheimer's

43:17 We also discussed fragile X syndrome under spectrum disorders. Okay, today we're

43:26 talk about multiple sclerosis. And I in this course, will remind you

43:34 about this disease, what it conjures in your mind, you when you

43:39 about multiple sclerosis, are you thinking young developing Children, adults, middle

43:46 adults or aging population and multiple sclerosis is typically in the 30s. So

43:55 a it's an adult. It's a adult disease. Typically with the onset

44:00 the 30s, it is not to that there's no early onset Alzheimer's which

44:05 before 55 and before 15. So not to say that there's no early

44:11 of of multiple sclerosis. But for most part you will see the symptomology

44:17 and the diagnosis of this disease In 30s systems. It's very different from

44:23 acts. It's very different from Alzheimer's as far as the onset the time

44:28 onset, typical onset of this It's an auto immune disorder. And

44:36 have to have in one of the in the genes. You have to

44:41 two bad aliens in chromosome 18. it's recessive. It's autoimmune. Which

44:49 that it is killing its own It is dim eliminating because it is

44:59 myelin, this is in the central system. Multiple sclerosis is in the

45:04 . N. S. We will about a disorder and PMS called shark

45:08 marry tubes. This is in N. S. Illegal Denver sites

45:15 what is happening in multiple sclerosis and is also similar to tremors. You

45:27 tremors and you have spasticity and muscle and sometimes convulsions and multiple sclerosis because

45:36 illegal underside myelin is being recognized as foreign invader and immune response is to

45:46 the myelin causing the auto de Myelin . Right. Uh This shows a

45:55 pectin normal genes. So this is gene trance faction of gene therapy if

46:00 may where you can recover partially some that myelin that is lost due to

46:06 genetic mutation. And so when we animal models, typically we want animal

46:13 to be really good models of what's in humans. There's a lot of

46:18 we cannot test in humans ethically, we can try to understand in animals

46:24 testing animals. And so animal you want to have the same mutations

46:30 humans would have in the same You want to have the same symptomology

46:39 or spasms and multiple sclerosis. And then it becomes a good

46:45 And then you can start testing therapies it's a gene therapy or chemical therapy

46:51 some sort. And seeing if first all an animal, if it improves

46:55 condition and hopefully taking into clinical trials see if it improves in humans.

47:01 there was a question in the back me. So like that's a great

47:10 . I mean, so one thing I haven't mentioned it at the very

47:14 of this slide is that there's multiple that the imagination can happen. And

47:20 way is that you can cause with infection and super myelitis and through information

47:28 can lead to do my elimination. some of the infections in the brain

47:34 syphilitic infections that are severe and cannot controlled. For example, they could

47:40 to the Myelin Nation. And in infections for example there are ticks that

47:49 as a colitis. And in certain certain countries in certain areas during breeding

47:56 , it can be really dangerous actually hospitalization of quite a few people with

48:01 . And it just depends what the is, the individual's immune response,

48:06 far the infection, the load of virus and so on. So uh

48:13 . Um if you have neural degeneration have everything you have d my elimination

48:22 neuro degeneration. But this is unique the sense that it is autoimmune.

48:27 there's multiple ways that this demolish nation a term But not multiple sclerosis is

48:36 the genetic component is inherited and I there's both sporadic and inherited and this

48:52 not only location for this mutation in 18, there's other mutations that are

48:57 with MS2. This is just an of it. Um Or so I

49:20 confess I have really poor hearing. have partial hearing loss and in one

49:26 my ears. So I didn't hear first part and that's why I asked

49:31 to repeat. I'm not being alright, walk up closer. I

49:35 want to intimidate you but I just hear very well. So I

49:39 The first thing is my elimination, constant process is the renewal of my

49:48 nations. A great uh question there outgrowth of new axons. But that

49:58 mostly during the development. That there's just maintenance of that myelin in the

50:05 . Oh okay. Let me move to the next of these. Which

50:12 shocked about married to. And in case and when we talk about these

50:18 basic proteins, it's not that it's lack of protein. Therefore there's a

50:22 of myelin. This is an example there's too much of peripheral Myelin

50:28 Otherwise known as PM 22. There's duplication of chromosome 17 producing too much

50:36 this program which also leads an abnormal Nation. Now when we talk about

50:42 attack, marry tooth disease, the and the outward expression of the disease

50:51 quite noticeable. The person that has severe Charcot Marie tooth disease. They

51:00 their legs that are deformed and typically outwards and they're walking is not gonna

51:10 as much of a forward motion but sideways motion is difficulty in controlling your

51:17 and balance as you're walking. This in early development in Children. If

51:25 have this mutation they will have D Nation and the peripheral nerves and D

51:33 elimination loss of Myelin around the peripheral . What happens if you cannot send

51:38 signals, you cannot activate the If you cannot activate the muscles,

51:44 body is you're developing and forming your are growing and your muscles are

51:49 But if your muscles are not activated by the nerves, they will not

51:54 the bones and the side of the skeleton, not the side of

52:00 the skeleton. The bones properly. the only way to try to fix

52:07 is uh well we're not actually talking therapies right now. But the only

52:12 for multiple sclerosis or for alzheimer's. haven't talked about therapist. This is

52:17 non chemical therapy. You can put person in braces and if you do

52:21 early enough and this is specifically really the lower limbs. If you can

52:28 a person in the braces and lower and adjust those braces during early development

52:33 may preserve more of the proper symmetrical structure and allow them to have more

52:39 the forward motion. So that's uh Marie tooth disease. And so

52:46 S. You're talking about effects at central nervous system. So all the

52:53 undersides and here you are talking about nervous system. So she wants.

53:02 . I think I just did you this is due to the violation?

53:08 . Yes. It's too much of protein. But like I said,

53:12 doesn't mean too much. It's too of myelin. Too little. Too

53:15 myelin the protein levels. The ratios the interactions are more complex than

53:21 In this particular case it's actually overproduction the protein that leads to this

53:29 Okay, so here's the cast of of the glial sauce that we've reviewed

53:35 far. Let's talk about the blood barrier for a little bit here.

53:43 as the sides we talked about blood barrier when we started discussing the COVID-19

53:51 and we said the blood brain barrier the themselves and have tight junctions.

53:59 things kind of pass through these junctions type parasites surrounding them and then you

54:04 the astro glial processes. So the site empty is the other checkpoint here

54:10 the molecules to pass from the blood the brain. So we have this

54:16 here. So small molecules fat soluble because they can cross the plasma membranes

54:23 can pass through molecules that have their and facilitated scope transporters molecules have combined

54:31 certain receptors and chemicals they are going be able to find their way into

54:37 brain. We talked about if you lose blood brain barrier that happens if

54:46 have significant even infection with covid you have inflammation, you have infection

54:52 epithelial cells in the blood. That the blood brain barrier gets loose.

54:58 also talk about how hypoxia a lack oxygen and also contribute to this abnormal

55:04 brain barrier leakage and so the blood barrier lose blood brain barrier becomes leaky

55:11 and allows for things to be more be transferred from the block into the

55:20 . It's a good thing that we blood brain barrier because you know,

55:24 have things that go into the not all of them will go into

55:27 brain, even infections and things like , you know, chemicals or even

55:33 you consume something is food and a of that chemical could be harmful in

55:38 brain, but it will be staying the body not crossing over maybe.

55:43 it's also a challenge. It's also you're thinking about Uh drugs, so

55:50 challenge you in this course to start about things that you will be doing

55:54 the next 20 or 30 years. , how do people take typical neuron

56:01 for depression and anxiety or epilepsy or ? They swallow a pill? There's

56:09 like you don't open the box in brain, put it on clothes,

56:12 know, different boxes for different parts pretty neat, you know? But

56:16 you swallow a pill and then what to that pill? It goes into

56:21 esophagus drops into your stomach ph 3.3 , starts digesting, it goes into

56:32 gut micro villa starts absorbing it goes the secondary liver metabolism, all of

56:40 things happening later. Right? When take a typical uh painkiller like

56:48 ibuprofen or acetaminophen, Do you expect your headache or minor pain to go

56:54 within seconds or you know, it's , 20 minutes. So that drug

56:58 to go in, go through this , get into the blood and

57:02 you know, pain is here obviously going to be affecting in the

57:07 Now if you want the neuro drug drug from the blood has to cross

57:10 the into the brain and it becomes challenge. And so you will hear

57:16 Tv for example or any pharmaceutical drug if you see them for example for

57:22 or depression, like well if you this drug, you know, be

57:26 of the side effects which is constipation or pain swelling and rashes on

57:35 stomach. And and that is because a fraction of that drug that you

57:40 will get into the brain. But there's common targets between the brain and

57:45 body. So if you're trying to something in the brain, it's better

57:49 very specific that crosses the blood brain and a very efficient fashion but also

57:56 something that specifically in the brain. , the less specific molecules are targeting

58:00 brain, you're getting into the the more of the systematic or general

58:05 effects that drug may cause in the . So that's not the best way

58:11 get drugs into the swallowing. We about the virus can find its way

58:16 the nasal passages. The silken drugs small molecules. So there are some

58:23 sprays and there aren't even nasal sprays seizure but they're not very popular because

58:28 creatures of habit and comfort. Another way to get things in the blood

58:35 through suppositories, anal vaginal suppositories, we're creatures of habit and that's,

58:42 know, takes a lot more effort do that. But that goes directly

58:46 the blood, bypasses liver metabolism, the digestion. What else? Inhaling

58:54 in your lungs, it goes into lungs, goes into the blood,

58:57 doesn't get digested. So the time takes for the drug to take

59:03 If you're swallowing something, you're looking minutes, 10 minutes, sometimes an

59:08 if you're inhaling or suppository, you're at much faster time where the drug

59:15 take effect. But in the end a fraction of what you swallow will

59:20 into the brain. And this is you will hear so many associated side

59:24 with the brain medications and vice versa of the shared targets. You're taking

59:30 in the periphery to, you help your pancreas and there's a depression

59:36 is developing because there's similar signaling molecules receptors that are involved in in

59:43 in this whole system that's called the and the brain. Okay, so

59:50 future is yours in developing really precise specific drugs to treat neurological conditions.

60:00 in mind the blood brain barrier and in mind all of these unique formats

60:07 medications but which maybe it can be more effectively and maybe it can become

60:14 comfortable that we can have a different of delivery of these medications to be

60:22 . Okay, so this concludes our and glia. And we are moving

60:28 our next lecture which is 45. some of these slides at the beginning

60:34 over a lot because typically do a bit of the review. But we

60:39 finished this material and I'm a little behind like half an hour in this

60:44 or so. So I'm gonna try make it catch up the time.

60:51 we're gonna study neuronal number and addressed member and potential and the action

61:01 And you understand everything and more than wanted to understand about action potentials.

61:06 you understand how there's a different way understanding action potentials also. But in

61:12 all the action in neurons is at level of the plasma membrane, plasma

61:18 has an equal distribution of charge and the outside is possibly charged on the

61:24 of the membrane, it's negatively you want to call the outside environmental

61:29 zero neutral, no charge and miller or bowls and to sink an electric

61:35 the zero into the cell. Your meter which show immediately a drop of

61:41 minus 65 million. So with respect the outside the inside membrane of these

61:47 is negatively charged because of the accumulation of charge that will be discussing in

61:55 next and unequal distribution of charges will discussing in the next couple of

62:01 So, as we discussed, this action potentials were recorded in 1939 and

62:06 , there were very fast 1 to milliseconds and we needed to develop fast

62:11 in order to pick up that activity display that activity on the fastest

62:16 A lot of the action potential recording the circuit development came together with some

62:21 the U. S. Military and Navy uh developments that were taking

62:26 In fact in electrophysiology lab where I you all of this electrodes going in

62:31 and in the slice we use B C. Cable student to connect the

62:38 and different pieces of equipment and B C case. This is not on

62:43 test. It stands for british Navy Navy cable that was adopted between the

62:49 , the americans and the brits. was developed further during World War two

62:56 even more sophisticated circus that we could use in the lab. Okay,

63:00 action potentials are very fast, 1 2 milliseconds. That's what we needed

63:04 very fast circuits. And today before talk about resting membrane potential and before

63:10 talk about other things, we're going very briefly. Not so briefly,

63:15 we'll try to understand the circuit which the reflex arch, simple reflex or

63:22 the simplest kind of reflex pathway. also referred to as major stretch or

63:29 tendon reflex. And it's really simple understand. But this is good information

63:34 I'm going to ask you to know the test. So if you understand

63:38 signaling here, you can understand how cell subtypes will contribute to growth and

63:48 in this particular circuit. So if going to doctor's office and uh like

63:54 yearly checkup or if you're having some in the lag or if you have

63:59 neurological condition quite often the doctor may your knee. Okay this patella tendon

64:07 so they sit you down just like person and they tap it with a

64:11 mallets. And if you have good tendon stretch reflex, your leg will

64:19 up after the tap. So this a stimulus and this is the response

64:23 the stimulus and the input is this mallet. And then we have the

64:29 nerve endings that are in the muscle are in the in the joints and

64:34 . And they will feel this mallet the on the attendant. And through

64:42 muscle spindle will take up that information the dorsal root ganglion cells. So

64:49 . R. G. Songs, dorsal root ganglion cells are pseudo unit

64:56 salts, morphological E dorsal root ganglion will release excited glutamate and dorsal root

65:06 cells will have their selma's located outside spinal cord proper forming this bundle or

65:13 ganglia of the selma's of the dorsal cells. So here you have the

65:18 axon carries that information. This is integrated unit as the selma which is

65:24 outside the spinal cord and then it a central axis that will innovate through

65:29 dorsal side of the spinal cord, back of the spinal cord into the

65:34 cord and it can contact a motor . Okay, so modern Iran and

65:44 exciting modern neuron, this dorsal root cell by exciting modern neuron, which

65:51 a multipolar cell morphological e motor neurons acetylcholine and motor neurons will project that

66:02 onto the muscle, releasing acetylcholine and the contraction of the muscle. So

66:09 sensory cells are a parent. They're information from the periphery into the spinal

66:19 proper and the modern neurons are They're going from the central nervous system

66:31 cord proper into the periphery. So kind of activation is reported as Mona's

66:38 and it's this most simple kind of . Now this reflex means that if

66:45 sensory neuron is activated and it excites motor neuron, this motor neuron will

66:50 the muscle and cause the contraction of quadriceps of the extensive muscle. So

66:56 muscle can contract with once and as activated monos in africa activation. But

67:03 do we know about muscle function If are contracting biceps? What's happening to

67:09 triceps? It's relaxing If you're contracting triceps, what's happening to your biceps

67:15 relaxing. So for this reflex and the leg kick to be a proper

67:23 . What you need is you need make sure that this muscle is relaxed

67:28 this is your opposing muscle, hamstring . A flexor muscle is opposing to

67:33 extensive muscle. In this case that dorsal root neuron is going to have

67:42 not only on the mona motor neuron also on this black cell which is

67:49 inhibitory into neurons inhibitor into neurons which also multiple ourselves. And these neurons

68:00 release glycerine which is inhibitory neurotransmitter. this is the exception that we talked

68:07 . The major inhibitory neurotransmitter in the as gaba. Except for the spinal

68:13 where the major inhibitory neurotransmitter in these neurons, local network inhibitory cells here

68:22 gliding. So if the sensor neuron excited it's going to excite motor neuron

68:28 going to excite muscle cause the contraction dorsal root ganglion cells, excited is

68:36 to excite the inhibitory neuron which is to inhibit the modern neuron and assure

68:45 this hamstring is relaxed and the proper tendon stretch reflex and kick can take

68:54 . So for the task you'll actually responsible for dorsal root ganglion cells with

69:00 sido, una polar polar multipolar motor and interneuron. The neurotransmitters that they

69:07 and the best thing that you can is mark around the circuit and try

69:12 draw the circuit on your own without at the notes and then you will

69:16 really well prepared to answer all of questions. In reality you can have

69:22 of synaptic reflex and contraction of this but it has to involve multiple synopsis

69:30 Synaptic to be fully functional and fully to this stimulation here in the form

69:36 the maori and in the body we other reflexive behaviors. So also when

69:42 say reflexive behavior, this is a which you cannot control, meaning that

69:47 you sat there with your leg like and the doctor and the mallet and

69:54 said I'm not going to move the , I'm not gonna let the leg

69:57 , I'm not gonna let there's no power over reflex. It's going to

70:04 right? You may be able to it while it initiated and started happening

70:09 you're not gonna be able to stop initiation of that. It also means

70:15 if something is reflexive it doesn't mean it's not conscious to proceed. We

70:20 to have fast action potentials. We to have this reflexive behavior because if

70:25 step on the nail, the last you want to do is contemplate about

70:28 doesn't hurt. No, not that . Not that part of the foot

70:32 would really hurt. So when you about it. But if you immediately

70:37 withdraw your foot from that bad stimulus that pain, what do you

70:43 You're consciously aware. So these signals ascend up the spinal cord through the

70:50 pathways and to the higher surface of brain and will inform you that this

70:56 what happened. The reflex and then have conscious perception of that and then

71:00 will happen then will happen response that no longer reflects it. And the

71:06 is going to be pretty complicated. going to initiate a complex motor pattern

71:11 bending over to make sure that the that your foot is not damaged by

71:17 nail. You're gonna put a band , you're gonna call the doctor's office

71:22 make sure that there's no infection or so that's not reflective. But this

71:27 will be happening reflexively. Most of reflexes we have in the body of

71:32 . So an example of a complex synaptic reflex is the gag reflex when

71:39 you are when you're nauseous when that is created by either emotional or chemical

71:48 . That's a complex reflexes involved multiple in the brain and multiple centers in

71:54 brain to have that response over Is that the? Yes,

72:15 Inter neurons are interacted with with with nerves, two glasses. So actually

72:22 gonna end here today and when we back, we're going to delve into

72:26 nice membrane biophysics selectivity of the No ernst equation baldwin equations,

72:35 So you may want to remind yourself some of this good biophysics stuff but

72:40 than that, have a good rest the week and I will see you

72:45 on monday. See you all on so that you can be ready for

72:51

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