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00:04 Welcome to Neuroscience Lecture three. It's first lecture of us discussing some of

00:10 basic features of neurons and glia neurons numbers comprise about 10% of the total

00:21 of the brain cells. So glial are a lot more popular. There

00:27 much greater number of real south in brain than there are neurons.

00:34 despite this 10 and 90% if you at the scientific literature on neuroscience,

00:44 self communication on the brain circuits, will soon see that most of the

00:50 is being done on neurons And it's the reverse, 90% of the work

00:56 done on 10% of the neurons and of the work was done glia and

01:01 was historically the case for many years we discovered glia and neurons. And

01:09 is because glia which disciples into glue thought to serve a supportive role sort

01:19 like supportive cells, maybe maintenance cells the brain and we perceive neurons and

01:29 connections and neuronal circuits. The place the action took place the most important

01:35 for neural transmission for electrochemical communications, plasticity and so on. In

01:44 neurons in the brain are like chocolate in the chocolate chip cookie and you

01:55 have a cookie really. Chocolate chip without miglia without the dough. But

02:03 cookie is not going to be interesting having the chocolate chips in it or

02:08 . Peanut butter cups, whatever is preference is. And finally for us

02:14 be forming misunderstanding of of neurons and as we discussed in the history historically

02:24 . The gain in the brain is in the stand meaning that you need

02:30 stain the brain cells to reveal their to reveal their precise anatomy. And

02:39 are different stains that we've discussed. discussed the Golgi stain and we called

02:43 Golgi stain stands only a fraction of , only one to few percentages of

02:51 of the neurons. If you apply silver nitrate stain on the brain

02:56 only a small fraction of neurons are to pick up that stain. But

03:01 cells that pick up the Golgi stain reveal their precise morphology. They're

03:08 Rights are axons all of their So it's very useful in describing the

03:15 morphology but it will not reveal the network or all of the cells.

03:19 so to reveal all of this off the network. And to build what

03:27 call the site of architecture. The , architect tonic methods that dr comedian

03:32 unused. There was another stand called Missile Steam. This will stand unlike

03:39 stand will stay in all of the across the board and that kind of

03:44 you would want to use to describe stacking the geometry of the south,

03:49 density, the layering of the south the brain matter. The game and

03:58 brain is mainly understand because the rain spain is mostly in the plane.

04:05 a famous phrase from from chameleon So neurons and neurons really that different

04:17 the rest of the cells in the . And in reality there are certain

04:22 of neurons that are just like the cells in the body. You have

04:26 selma, you have the nucleus, have all of the other organelles that

04:31 have learned about. You have mitochondria which is a source of energy.

04:36 have poly ribosomes and rough and smooth plasma critical um where you have the

04:45 and translation off the pro dance and of the proteins by the golgi complex

04:54 reach their final destiny whether they're membrane or cytoplasm proteins. But then there

05:01 certain features of this neuron that are that you do not see in other

05:08 . And in particular it's the down . And if you look even closer

05:13 top of these dendritic shafts, you these protrusions and these protrusions are the

05:19 spines. And we talked about how modern day neuroscience we can actually visualize

05:25 spines is the site where most of connections and connectivity will take between the

05:30 . So most of the inputs from neurons will contact dendrites and dendritic

05:36 And the dreaded sponsors are also very elements. The most malleable elements,

05:41 that you can change the shape of spines. You can eliminate these

05:48 you can grow new spines and it the most plastic and easiest way for

05:53 brain to respond and to strengthen connectivity also to respond to the environment and

05:59 plastic. So rather than eliminating the process the whole done right. You

06:05 eliminate one or 2 spines or you add a few spines. So this

06:11 quite unique for neurons and it's You also have axons. Axons as

06:18 mentioned, will contact mostly done dried brittle spines, but also so much

06:23 the neurons and axons, their myelin So glia contribute to the myelin

06:29 which is essentially insulation of the action the axons. A cell will generate

06:38 action potential right here at the axon hillock. So this is also something

06:44 is unique to neurons. It has at the level of the axon,

06:48 segment the initial axonal segment or axon hill up is the place where the

06:56 potential is going to get generated all the information that comes into dendrites and

07:02 spines. Most of it or some it. It just depends whether these

07:10 are excited or inhibitory these neurons and spines will be receiving both excitatory glutamate

07:17 transmission excitation and also inputs from the cells that are releasing Gaba which is

07:25 major inhibitory neurotransmitter. And so the as they come into the done right

07:31 then don't experience and notice that there an optical down right here which is

07:36 the apex of this is a typical neuron that has shown because it has

07:41 pyramid like structure as the apex or peak. And this is the optical

07:46 right. And then it has the and off the base you have these

07:51 gun rights. So all of the coming into the dendrites and dendritic spines

07:56 then essentially get processed and integrated all that information into the south soma.

08:04 makes the decision. The selma makes decision. Together with axon initial

08:11 this axon initial segment, whether there enough deep polarization in this entire complex

08:17 to produce an action potential. And that action potential gets produced, it

08:23 gets conducted down the axon and the nation that you see. Myelin sheets

08:29 wrap around the accents. They act like insulation for the wires. So

08:35 happens if you strip the wire from cable, electric arcing over a

08:42 Exactly, electrical signal will leak And electrical signal may not reach what I'm

08:48 in the computer. That's the first would be abnormal traveling of the axons

08:55 leakage of the current from this Making the cells unreliable in their

09:01 Okay, so organ Al's and the processes. Uh, it's very

09:12 You have jeans, you have genetic , You have transcription. You have

09:18 code RNA. All right. RNA a messenger RNA. And this is

09:27 happening at the level of the nucleus inside the nucleus we think that there

09:33 these sort of like little busses, shuttles if you may that shuttle through

09:39 nuclear pores through these openings in the exporter shuttle this messenger RNA into the

09:48 and inside of plaza you have So transcription, gene code translation.

09:58 you're translating the messenger RNA into the . Mhm. This is your gene

10:05 you know you have entrance and Exxon's there is a process of transcription creation

10:16 RNA. And then there is a of splicing, mm hmm where certain

10:24 are removed. And during the splicing you get this messenger RNA that now

10:32 encode for a protein of interest. a receptor channel protein. This this

10:41 processes. During the splicing process you have what is called splice variants.

10:47 removal of the intron regions and reshuffling the entrance and axons may have a

10:57 variation during the splicing process. Splice may become proteins that have slightly different

11:08 to them, slightly different functions but very very similar to each other.

11:14 variants is what makes us different butt variants also can cause genetic translation abnormalities

11:26 in abnormal protein information causing neurological in case because we're talking about the brain

11:34 abnormalities of neurological disorders too. So is normal splice variants and there's pathological

11:43 pathology that can be associated with splice . But this process is very basic

11:50 that you've learned in high school We're not going to be reviewing many

11:56 about some of these basic things organelles as rough and the plasmid particular um

12:03 have the ribosomes, you have the up in the plasma articular, you

12:08 ribosomes surrounding it. You have polarized and complexes. Once this messenger RNA

12:16 out, it can then be created a protein. And that protein can

12:24 cytoplasmic, meaning it's a protein that destined to floating around the cytoplasm.

12:30 in some instances there is newly synthesized that embed themselves in the plasma membrane

12:38 their membrane associated and they may be membrane channels. They could be just

12:44 on the membrane on the inside of cell. But these are basically the

12:49 major pathways membrane balance and Frida side solid floating proteins. What we No

12:59 and again, you'll probably hear much explanations if you're taking genetics or if

13:04 taking uh cell biology, you may things as jean micro race and what

13:13 jean micro race and what is jean array profiling. So we live in

13:19 post genomic era, meaning that we we know that the gene code and

13:25 think we know what the gene code for. And by the way,

13:30 of the cells, all of the and all of the cells in the

13:35 and this nucleus will contain the exact gene code as the other cells.

13:41 neurons will contain the exact same gene as lee ourselves. Same gene

13:49 There's a heart muscle cells but during transcription process, of course, only

13:55 subset of these genes get expressed. that's how you get A variety of

14:01 to 250 or more different subtypes of in the cns. It's a subset

14:08 genes, potentially splice variants also that to the subtyping of different health.

14:16 we know what the code is. know what the code Codes four.

14:21 now we can make a synthetic code synthetic DNA. And you will see

14:29 around the university. How many base you want? We can create uh

14:39 a strand uh if you're liking basically they charge you, you know

14:47 per megawatt based mega bass or something that. But the because we know

14:55 and because we know what things go . There are these things that are

15:00 micro race and they're really just just small microscopic plates And these microscopic plates

15:07 contain thousands, 10, 20 30,000 wealth in them. So these little

15:14 micro welds a little openings. And you do is you load up these

15:20 wells with your synthetic DNA with gene sequence. So you know, 30,000

15:32 . And you know the sequences 30,000 that code that that sequence codes for

15:39 in jeans. No, you lay of these. There is commercially made

15:45 arrays or synthetic DNA in it. , what you can do is you

15:52 have a bird's eye view or an of what are the gross changes,

15:58 are some of the big changes that happening? And you can take brain

16:03 and brain to and let's say that brain one is normal and bring to

16:10 is a bill optic brain for So it's an abnormal brain that has

16:17 neurological disorder. So you take the , one is labeled in red.

16:23 take another vial from the brain. you put the brain tissue in

16:28 Okay marginalized. Do the whole procedure labeled green and you mix the two

16:36 apply to D. N. A right? So the gene that has

16:42 expression and brain too will show up red And the gene that has reduced

16:51 in brain. one will show up green genes that have equivalent expression.

17:01 will show up as yellow. Okay no change. Okay so what have

17:07 done now now you have analyzed and to two brains and because you have

17:14 different stands the red and the you know which one is coming

17:17 which brain? Now that molecule of that is in the brain is applied

17:26 this solution is applied into the into these micro wells. And these

17:33 have a synthetic strand of DNA with specific sequence look at it as a

17:39 complex velcro piece of velcro and that piece of velcro needs to match an

17:45 piece of velcro to precisely fit into . If it does, then it

17:50 harbor more and more and more and show that there's more of that gene

17:54 less of that gene express. So is a really good technique. Now

17:59 compared brain one on brain too to a bird's eye view of the changes

18:04 the whole brain wind the whole brain you have homogenized brain tissue, unless

18:12 gonna take one structure from the brand , you're gonna compare once they're a

18:16 , healthy cerebellum too and neurologically impaired epileptics are available but you'll still just

18:23 about cerebellum. So you will not about specific cells necessarily, but you'll

18:27 about the genes. And now when get a result from the micro

18:33 you will get hypothetically 200 genes going 500 genes going down the expression then

18:45 going to say, well, That's great. But that's a

18:51 And I cannot even do my PhD one gene, there's 201 up 501

18:58 . What do you do that You say? Okay, well in

19:01 , we know That out of 300 up 500 down and epilepsy,

19:07 know that these 50 genes are extremely for epilepsy because we're looking at epileptic

19:14 And we know that from other studies there's models, there's genetic models of

19:19 . So 50, okay, that's . Right? And from these

19:25 25 went up 25 went down, see what is what is important.

19:33 you're gonna say, well, which went up the most? So out

19:37 this 25 at one top you'll Oh look at these, The 11

19:42 two actually is 200 times the normal And the others are maybe just 20

19:50 of the normal expression. So you say, well maybe it's this because

19:55 like so prominently over express this And then you look at the other

20:01 that's under express and you say maybe those bottom ones that are the lowest

20:05 expression levels are the most important. you may be right, but there

20:10 a sequence also in jeans and there's sequence in what the genetic expression and

20:18 ends up in the interaction of the downstream. So then your boss will

20:24 , I'm interested in these five genes you have to do your PhD on

20:29 too. And so then you're gonna and do about half a year of

20:35 and literature analysis and stuff until you're end up picking two out of those

20:39 genes and pursuing their further studies. micro rates are very useful to give

20:47 complete bird's eye view of the major . But when I say that you

20:54 say that the thing that changed the is the most important thing because there

20:59 be a precursor gene that leads a change that leads to this big

21:04 And the sequence of advances small change precursor change is actually more important than

21:09 this very large change in another Smooth. And the plasmid reticulated is

21:18 you have put in folding and calcium . You also have internal calcium

21:26 And in neurons you heard another south . And calcium regulation is important in

21:32 . Calcium is not only a Evelyn catty um It's also a secondary

21:38 . And the neurons you will not free to set a solid calcium floating

21:43 in high concentrations. Most of it bound up and most of it is

21:49 bound up. And if you have side of solid calcium it can act

21:54 both the physiology changes in the number potential levels as well as as a

22:01 messenger in the intracellular cascades. And very tight regulation of calcium inside

22:06 Special inside neurons Golgi apparatus is where have post translational processing and protein sorting

22:13 determine their final destinations. You learned crab cycle in high school and so

22:24 I. And then I learned Krebs in college and so will you.

22:32 then I learned crop cycle in graduate and every time I learned Krebs cycle

22:39 was learning it like renew. Again it's pretty complex actually. And then

22:47 not going to talk about the home chains and all of these things.

22:54 you should know that most important thing this organ al's that our mitochondria the

23:01 of energy in the body and the they produce the denizen triphosphate which is

23:06 peace. Denison is not only a of the denizen triphosphate for A.

23:15 . P. Dennison. Di a dennison is also a neurotransmitter neuro

23:20 in the brain. And so we understand the denison function. So denison

23:24 the brain is what makes you So eight ep gives you energy and

23:29 you. But if you take a core molecule of ADP a dentist in

23:33 dennison by itself makes you sleepy and which most of us had this morning

23:41 the form of coffee chai, tea or whatever else. Caffeine also acts

23:49 the dentist and receptors. So you this mechanism today is just a teepee

23:55 source of energy. You have this interesting structure. The outer and the

24:00 membrane of the mitochondria. Um With imaginations that are called Christie and you

24:07 have dietary and stored energy sources. the more active neurons are, as

24:13 was telling you about the brain maps those hotspots that you can visualize in

24:17 brain, the more active, the are, the more energy and oxygen

24:23 going to draw to themselves. The protein, sugar and fat they will

24:30 glucose and they will through conversion peru acid and oxidation will produce ATP And

24:39 . 0. 2 and the brain a system that is driven outside of

24:48 normal equilibrium because brain brain waves only 3 1/2 or so. And it

25:02 only a couple of percentages of your body mass depending on on the on

25:09 body mass. Remember we're not for , so we're not going to call

25:14 , small, small headed people as and big headed people as geniuses.

25:21 ? So so we have this arrangement it's just a fraction a few percentages

25:27 the total body mass And the brain 20 of the total body energy.

25:38 why it's a system that 3% doesn't for 3%. is asking for 20%

25:44 total body energy. So 20% of you're eating, breathing, drinking,

25:56 synthesizing, metabolizing in the body. goes through the air conditioner of the

26:07 very high, very high energy and very high metabolic demand. In other

26:14 , neurons require a lot of A lot of energy to be active

26:19 your brains are not in active when sleep either. You're consuming a lot

26:25 energy during sleep. Your body is moving well. In some cases you

26:31 moving and maybe even talking but it's to a certain phase of the sleep

26:38 . And in general, what you to think about is this membrane that

26:45 neurons is very fluid ISSE. And this goes to the concept of plasticity

26:52 the ability for the selves to rearrange structurally and also functionally there's this dynamic

27:01 mosaic model of the plasma membrane which a phosphor olympic bi layer. You

27:08 the polar hydro cilic ahead and then have the hydrophobic fatty acid chains that

27:21 on the inside of the membrane. it's a fossil lipid bi layer.

27:26 have carbohydrates, you have fat cholesterol in their foster lipids, lipoproteins.

27:33 have trans membrane proteins. Some of trans membrane proteins are channels which means

27:39 will allow for the passage of And that's how fast signaling across plasma

27:44 in neurons happen. And other there proteins that are not channels. So

27:50 may be g protein coupled receptors that downstream through the signaling cascades, cellular

27:58 holding this phosphor lipid bi layer is of skeletal elements and these side of

28:07 elements can rearrange themselves. So, the side of skeletal elements become

28:14 they depolymerization or they become longer problem chains because a slightly different structure and

28:23 different fluidity around the surrounding membranes. , I'd like to show this very

28:31 video of a fluid mosaic model. discusses just that improving the living machinery

28:45 the inner cell and the harsh conditions the outside world stands themselves. Plasma

28:52 as crucial as this barrier is. surprisingly flexible. What's your name

29:05 Remember actually assembled into a double play their tails with no water is there

29:12 attractive the ones on cholesterol and a trouble. And you have the basic

29:19 of the. Mm hmm. We find giving programs various questions for

29:29 For instance, they received signals from world outside where they transporting nutrients in

29:37 . So nature composes the membrane and molecules are last dictionary. They constantly

29:51 infrastructure, position. The survival of life rests on this veil of interior

30:07 . So the molecules the membrane this is and the molecules even trans membrane

30:13 that are embedded in they move through membrane, they constantly change their

30:20 And in neurons this movement can be fast in neurons, proteins can move

30:25 meters in milliseconds, micrometers and Remember that the diameter of the selma

30:33 the neuron is 10 micrometers. So talking about proteins that are entering into

30:41 parts of the number rains and this is influenced by external activity. So

30:47 is a certain type of you can steady state amount of this fluid this

30:53 and then once you have heightened levels activity, there is a lot more

30:57 going on with these protests across plasma and the site of skeletal elements that

31:03 underneath are also moving. And that's you can change the shape of it

31:08 didn't spine because you can change the studs that are holding up the house

31:16 the floor and the ceiling of the that dendritic spine. and the studs

31:22 be like the side of skeletal So you can do a rearrangement in

31:26 house, you can remodel the house make a third bedroom and you do

31:31 by you know adding a stud and some drywall in it. And so

31:36 is what the dendritic spines do. rearrange themselves structurally the survival of all

31:47 rests on this veil of material Just to acknowledge that between the living

32:12 . So the fluid mosaic model and the sight of skeletal elements, you

32:16 three types of micro two bills, elements and micro filaments. You have

32:24 micro two bills that are comprised of turbulent molecules and there are about 20

32:29 in diameter neuro filaments are about 10 in diameter. And the smallest elements

32:36 the micro filaments that are comprised of active molecules. So the more of

32:40 active molecules to aggregate the prelim arise chains. And you can also depolymerization

32:46 break them up into smaller chains. is a cross session section through the

32:54 . And what you see is first all this this area here that looks

32:58 of like a channel. If you you're used to looking at the sonar

33:03 from depth finders, it looks sort like a channel and then these are

33:08 edges of the channel and these edges the channel. You can see these

33:12 lines and these are myelin sheets. is my elimination that is found around

33:18 but inside the axons you see these like strings like over here it looks

33:26 sort of a spaghetti running across These are micro tubules and these are

33:34 we refer micro tubular highways. So a lot of transport, active transport

33:44 proteins, peptides, things like that happened along the micro tubules. So

33:50 that get made in the soma or that are in the periphery and need

33:56 be recycled back to the soma. travel along these micro tubules and so

34:03 have parallel pathways for these micro tubular that that carries the information and the

34:11 of these active molecules to become shorter longer. You can think of it

34:17 the side of skeletal elements causes the of the plasma membrane that they're

34:22 So if you rearrange the structure you're also going to change the shape

34:27 the dumb driver dendritic spine and if change the shape, you're going to

34:31 the levels of its activity. Also structure and function are intertwined,

34:41 This is an example of a stained stain which is tubular lint, the

34:49 state which is active and in purple have the nucleus and this is a

34:56 cell. It's just as an example using the spider blast self and it

35:04 you something, it tells you that larger elements, the largest side of

35:10 elements are located around the nucleus. is really supporting and protecting that structure

35:18 the nucleus. But the smallest the active molecules that comprise micro filaments

35:29 and you can see that there's arrangement all three of these side of skeletal

35:34 . So they're intertwined. But on micro scale, you see that the

35:39 molecules in blue are located at the edges on the outskirts of this

35:48 I envision each neuron or each cell a city. It has its

35:53 it has highways going in and has of communicating. And it has these

35:59 boundaries or in old medieval cities, walls and in neurons. These walls

36:07 plastic. And so you can see these small elements that are in the

36:13 periphery closest to the plasma membrane. changes in the structure underneath would then

36:19 the shape, overall change in the and the surface area of the plasma

36:32 . I thought I changed the slide it keeps popping up again. I

36:37 am not a fan of the So, let me today, we're

36:45 to introduce our first neurological disorder and introducing it here because it kind of

36:53 sense with certain aspects of some morphology anatomy that we're studying. What I

37:02 for everyone in this class to do to make a page in your

37:11 maybe at the end in the middle your notebook, a neurological disorders and

37:18 make a page and dedicate one page Alzheimer's disease. And then when we

37:24 about multiple sclerosis, dedicate another page multiple sclerosis. And when we talk

37:30 epilepsy, dedicate another page to So when we talk about autism spectrum

37:39 , Dedruction Page, two authors expected . You will be learning terminology and

37:44 little bit of that terminology will be terminology to in understanding these neurological

37:54 And uh, what you're seeing here a slide on Alzheimer's disease. The

38:05 hallmarks of Alzheimer's disease. Remember what said, neuropathologist study neuropathologist study changes

38:14 brain tissue abnormalities of normal stains and on. And brain tissue.

38:22 what you're looking here on the left a normal brain, normal neurons and

38:30 the right, you know, looking mm hmm. Great on the

38:38 you're looking at the brain both in image is a B and C.

38:43 the right. You are looking at brain that has severe Alzheimer's pathology.

38:51 , there's certain things that we may to know and understand when we talk

38:57 neurological disorders is Alzheimer's disease and developmental . There's Alzheimer's disease, a normal

39:06 of aging. When do you think disease is more prevalent than twenties

39:14 fifties, sixties seventies eighties, the you are, the more likely you

39:22 to develop Alzheimer's disease, it's a , it's not a normal part of

39:27 . So when you talk about first of all, what is the

39:33 that you're talking about? Alzheimer's is is a form of dementia. So

39:43 is how you define Alzheimer's is a of dementia. Then you will

39:49 okay, so what do people experience they have Alzheimer's disease? And when

39:56 talk about what people experience, you about, what is it you talk

40:03 pain? Is it pain, loss memory, confusion, anxiety,

40:13 disorientation. What are these things? mechanisms of action these symptoms? Somebody's

40:24 things. You're observing it as a and then you're forgetting things every

40:29 Say something is wrong. I'm trying to forget what I'm forgetting. Then

40:35 a symptom. Mhm. So once patient has that symptom, what is

40:45 on in the brain, what is pathology? What is the mechanism behind

40:52 disease? Alzheimer's disease? You have hallmarks. Pathological hallmarks. There is

41:02 formation of amyloid plaques that are also to as beta amyloid plaques.

41:11 I'm glad you guys are taking notes they typically will have to to a

41:16 questions on neurological disorders in each And I may ask you is amyloid

41:26 , the neural liberally tangles. They're of the Alzheimer's disease pathology. And

41:31 ask you abnormal dendritic spine density? that a part of the Alzheimer's disease

41:39 ? Is it one of the Well, so you'll have to know

41:43 information. So we're getting to? won't be studying this today in great

41:55 and as far as the abnormal protein and how it's happening and such?

42:00 also the reason why I want you leave a page is we'll be coming

42:04 to Alzheimer's disease. For example, we talk about neural transmission and we

42:09 about acetylcholine, we will talk about pathology and loss of the colon ergic

42:16 , but we will not do it . We're going to have a gross

42:19 understanding of Alzheimer's disease is. But a few lectures later, you can

42:24 back to that same page on Alzheimer's and add more information on the chemical

42:30 and that specific subtypes of cells that involved when data, amyloid plaques

42:36 They referred to as senile plaques they to as calcification, plaque. Sometimes

42:43 abnormal aggregation and calcification of proteins on outside of the south. This is

42:49 hallmark. The second hallmark is intracellular this is the formation of neuro february

42:57 tangles and there's proteins that are We want to discuss them. But

43:01 a towel pro dam that causes the tangling of neurofibromatosis. So what happens

43:11 you tangle up the side of skeletal . I just told you about external

43:17 , how the goods and information gets in the same within the same

43:22 So what happens if you cannot deliver or food to one part of the

43:30 , those people will not survive. that damn drive will not survive and

43:35 may not survive because the tangles. you've taken up and these highways that

43:40 have with the lights that people follow traffic and take the turns all of

43:44 sudden they're all on top of each and intertwined and inter tangle. So

43:49 of all you have an ability to things and to have inside the cell

43:58 , entrust cellular communication that gets 2nd of all this amyloid plaques on

44:06 outside, they start physically physically causing in the tissue. So it's not

44:13 that they formed and they're sitting they become like little balls of inflammation

44:20 they start growing and aggregating more proteins debris and then they start affecting axon

44:28 segments in particular. So what happens the amyloid plaques is they physically start

44:35 parts of the Acts on initial segments now the cells cannot produce action potentials

44:41 . So you have two problems on inside of the national february tangles will

44:48 an ability for intracellular delivery of intracellular communication. But if you cannot

44:56 things to the distal parts of the , you also cannot receive things

45:02 And on the outside these amyloid plaques start damaging axon and remember that axon

45:09 that axon initial segment, it turns that that accident initial segment is extremely

45:16 to the extra cellular plaques And it's sensitive that only 10% reduction in its

45:24 Can cause upwards of 30% failures and potential generation. So to answer your

45:32 , the mechanisms are complex but mostly the cell. It has to do

45:37 intracellular communication, nutrient supplies inside the and outside of the cell. It

45:43 to do a lot with the synoptic and the production of the action

45:50 And if you look on the gross scale, which is our image here

45:56 the right severe Alzheimer's pathology is causing neuro degeneration. So you will hear

46:08 disorders. That means that there is and loss of neurons and loss of

46:16 tissue. And you can see massive on a gross scale in Alzheimer's

46:24 there's a massive reduction, okay, shrinkage off the gray matter but the

46:32 brain is completely different shape. Now you go to a doctor and you

46:42 advanced state of Alzheimer's disease, can tell you that you have plaques in

46:47 brain? Can the image that we're there? We're getting very close to

46:52 to image the plaques in the brain invasively in the clinics. But that

46:59 already a very advanced stages of the . In reality. The ultimate diagnosis

47:06 Alzheimer's disease can come postmortem postmortem after when you can actually look at the

47:15 tissue and say now we confirm definitively plaques, tangles, neural degeneration shrinkage

47:23 the brain before that whatever you're doing symptomology is a neurologist or the patient

47:30 with neuro imaging it's it's still quite for the definitive diagnosis. And so

47:39 is a progression of the disease progression the disease and the symptomology does it

47:44 happen if the person just wakes up they're completely confused and remember anything.

47:49 usually is a gradual onset and development these symptoms. Now when you start

47:55 your grandmother is forgetting your name once month and then the grandmother is forgetting

48:01 name and confusing you with another person time you see her something is going

48:07 . And so they're very interesting studies older people that are keeping themselves mentally

48:15 that are keeping the speech areas and writing active. There's some very interesting

48:21 of nuns that seem to live in environments. So they don't have that

48:26 of the stimulus, you know, to be plastic to all of these

48:31 by the outside world. But they reading and writing extensively and they have

48:37 , very low incidences of of So this disease progresses and it may

48:45 in some instances as early as 50's it can progress and when the brain

48:53 are dying and you're forgetting things. are then at the end stages of

49:02 disease, the brain is no longer of taking care of the body cannot

49:08 because you have to have a neural in order to swallow. So you

49:12 feed and at some point there's no , you know, mechanisms that get

49:17 . So we will come back and more about Alzheimer's disease in this

49:23 This is not the last time we about this and I know you will

49:27 questions throughout. Go ahead. Is how it kills a person? Because

49:33 you're not able to. Yes, it's first the conscious cognitive memory and

49:42 it's some of the basic body functions the plaques, the infiltrate throughout the

49:50 brain tissue. And they can start the hippocampus of the cortex and then

49:55 migrate throughout the brain and spread and of a multiply and you can find

50:01 everywhere. And if it starts affecting inflaming some of the brainstem regions that

50:08 responsible for vital body functions and You those two. No thanks.

50:16 Okay. I think this is the window. Mm hmm. This is

50:27 dendrites and dendritic spines. And this the axons and all of this has

50:32 have precise anatomy. The dendrites and . Axon initial hilo. It should

50:37 action potential in normal functioning brains. there's a some terminology here. So

50:46 hillock here we are. Action potential produced. Axon collaterals actions don't have

50:53 terminal synapse actually can send off branches terminate on many different neurons. Accident

51:03 button. Or if you french inquired . Ah They're referred to as Bhutan's

51:10 present. Or buttons and passing axons leave these little connections and buttons as

51:18 travel through until the regional terminal side connectivity. The area between the axon

51:27 the dendrite or the selma is a inside synopsis and then side next channel

51:36 . You see a lot of So there is a lot of energy

51:43 that are necessary for the vesicles These are the vesicles that stored

51:50 The neurotransmitter vesicles will fuse with the membrane and release neurotransmitter content into the

51:58 cleft. That space is about 20 apart. Okay physically Chemicals will travel

52:09 the space. 20 nm and the synaptic side you have receptors that we

52:16 to earlier as PTSD post synaptic That means there are collections of receptors

52:22 are densely located and are juxtaposed directly from the input from the axle

52:32 So we'll know a lot about synaptic . Will know a lot about different

52:37 . Not just glutamate and gaba but and dennison, norepinephrine and all of

52:45 other good stuff that we found in brain and the peripheral as well.

52:50 hmm axel plasmid transport axons as I we'll use these micro tubular highways and

52:59 is engines, motors such as knesset opposite direction. That's dynamic connection will

53:07 and terror gravely from selma into the . Then we'll carry vesicles will carry

53:14 will carry some of the other things of pass it along along the

53:20 And so there's your answer to what if you tangle up these highways.

53:25 of a sudden this transport is hugely retrograde direction. You'll have a different

53:32 that carries his dining, You have of plas Mick transport. And in

53:38 early historical days, we used to up an axon, inject the

53:43 tie up one end of the accident see how long that diet takes to

53:47 through the axon in the lab. , those were the early experiments with

53:52 dies. So 1 to 10 a , 10 millimeters is one centimeter one

54:00 is two point five cm. Something that. And then you have fast

54:07 of plans and transport like you could that using radioactively labeled nucleic acid

54:15 And there's 10. The day fast millimeters. Ramirez is a centimeter 100

54:29 10 cm. 1000 is one So that is fast Now. What

54:35 you are Dwight howard? Mm Who is now the center of

54:46 I know, I don't know Who is on that team actually.

54:52 the point being is that there's some long axons. There's some very long

54:57 men and women that have long axons the transport, you know, we

55:01 it fast. But it takes a to travel and meet her in some

55:07 . So this transport is important and transport is nutrients and vesicles and things

55:12 happening in addition to the fast electrical that are traveling down through the

55:19 Mhm. And we have these We can use tracers, retrograde transport

55:29 particular. Retrograde means it's going to transported from the periphery or from the

55:35 endings into the selma's. So you a question which part of the

55:41 Like what neurons are connected to this of the scandal? Let's say it

55:46 be another network of cells. But just use the skin an example.

55:49 you take a horse riders peroxide is one of the dyes that will travel

55:54 lit and the dye will get taken by the nerve endings here in the

56:00 . So you injected the dye here then you'll say oh it's this network

56:04 H. R. P labeled neurons is communicating or taking the information from

56:09 patch of skin. Alright, there's nerve endings that from here go into

56:15 neurons. It's really nice way to advantage of the interrogator and retrograde transport

56:21 label things to label the projections across brain. We also have herpes virus

56:28 can use retrograde transport to enter into soma rabies virus. Mhm. We'll

56:39 about Herpes Zoster virus when we talk shingles, Herpes, Zoster has the

56:44 to travel both answer greatly and retrograde . So some viruses have the ability

56:52 do that too. But why do care about this? Because we want

56:56 know the connectivity of the brain. we want to know where are all

57:01 these connections between neurons. And we to know retrograde and interrogate fashion.

57:06 want to use all of the virus too because you can tag viruses with

57:11 label and you can see how that will travel through the cell and that

57:15 light up this cell as it travels let's say a fluorescent lee label the

57:21 virus and dendrites and dendritic spines. elements that if you change the site

57:29 skeletal arrangement underneath the plasma numb plasma membrane is fluid as it's going

57:34 rearrange itself. Mhm. These spine , first of all, you have

57:43 lot more spines and synapses when you born and when you end up in

57:47 adult years. So there's a lot dendritic dendritic synaptic and spine pruning clipping

57:54 going on during the refinement of these into the adult brain. These spines

58:00 also contain synaptic polar ribosome complexes and loaded with eight p. Why would

58:08 have polar ribosome complexes in dendritic Because that makes them critics find biochemical

58:17 from the soma and it's located very far away from the summer. So

58:21 it needs to do something locally translates locally, it can do it at

58:27 level of the dendritic spine independently. has a certain level of independence,

58:33 some decision some translations from the settlement these spines come in different shapes and

58:42 . They have to have precise density along the dendrites and this process is

58:49 and environment dependent process. You can the spines. You can grow new

58:55 . You're now taking notes, You're some dendritic spines. You may be

59:00 new dendritic spines. You're going to the information. You're going to strengthen

59:04 dendritic spines. You're gonna repeat it times. You'll never forget it.

59:08 dendritic spine. They stay there for , many years. Mm hmm.

59:13 this is activity dependent environment dependent You you start doing different tasks.

59:20 start changing the spines in different parts the brain in a different way.

59:25 using different dynamics. So arrangement of spines and densities of dendritic spines are

59:34 important. We're actually going to end lecture today because when we come back

59:45 thursday and please remember on thursday I only be in zoom. You're welcome

59:50 come to class. I just will this rule for the first two

59:54 Welcome to come to pass to watch video on zoom. Um When we

59:59 back we will talk about mental retardation autism spectrum disorders. And so we

60:06 about six minutes today and I don't to rush through it. It's a

60:12 important topic and it's in a completely age spectrum from Alzheimer's disease and it's

60:23 to dendritic spines and dendritic spine densities dendritic spine formation and normal synaptic formation

60:29 plasticity and developing brains. Okay, why? It is important that we

60:35 more than five minutes On it is currently about one in 40 boys are

60:46 diagnosed with what we call autism spectrum or asd, autism spectrum disorders,

60:54 is a broader umbrella for developmental and representations and different syndromes that fall under

61:02 umbrella. And this has been changing the last decade. From one in

61:11 boys, one in 70 girls, now, one in 40 boys that

61:17 being diagnosed with A. S. . And so I would be interested

61:23 maybe have that discussion on thursday a bit and see if I can bring

61:30 some interesting statistics and also talk about of the mechanisms and pathologies that relates

61:35 dendritic spines. one in 40 in country or. Yes. Do you

61:43 the prevalence is actually increasing or the ? It's a very good question.

61:49 getting smarter with the diagnosis. Of . Uh maybe we're paying a lot

61:54 attention to those things. But I think the world is changing and I

62:00 the world is changing in my opinion , you know, a lot of

62:04 autism has to do with the social ability to communicate with others and be

62:09 part of the just, you a pack, so to speak.

62:14 I think that is changing with I have a prediction is going to

62:18 autism a lot because families have been to be together for the last two

62:23 and the whole year, they stayed at home so that child that had

62:28 supervision or had no stimulation. I not enough loving care from the parents

62:33 could be one of the you things that lead or at least contribute

62:39 progression of autism. Then those things changing just like with pets, you

62:44 pets got used to having their owners . But then when the owners have

62:48 go to work, the pets are anxiety and they're freaking out. It

62:54 . Yes. Could it also be opposite? Because Children don't see like

62:58 facial expressions or hang out with people own age. It's either that and

63:02 a very interesting topic as a But I think we learned how to

63:06 people's eyes much better than the last years to and recognize maybe even fake

63:12 with ice. You know, people go ahead. Dendritic spines.

63:28 Dendritic spines would have their own sort a separate biochemical machinery which would require

63:35 mitochondria and 80 p. And which require polarized assemble complexes too. So

63:42 locally without informing the major dendritic without informing the soma that dendritic spine

63:49 make a decision. I can rearrange and there's other elements that you learn

63:54 that can help that rearrangement too. I have a full of questions with

64:00 . So does that mean the complex and come running A. M.

64:06 locally for for use precisely. Yes. Great questions. Thank you

64:15 much. Thank you all for being . Thank you

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