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00:01 We could lecture four of neuroscience and we talked about the site of skeletal

00:07 , we're going to actually introduce the . Our first neurological disorder that we

00:12 in the scores and that is Alzheimer's . Right. And so you'll see

00:19 this is related to Cida scalp elements just a minute. But before we

00:23 that and talk about the mechanisms or cellular mechanisms, the pathology of the

00:29 . With this slide illustrates illustrates that marks of the pathology of Alzheimer's

00:37 And when you think about alzheimer's you have to start thinking about it

00:43 many different angles and many different So you may have a perspective of

00:52 disease where you have experience or you somebody or you have somebody in the

00:59 that have suffered has suffered this suffering Alzheimer's disease. And when you think

01:09 Alzheimer's disease, the first thing you to think about, Well what is

01:15 prevalence see and what is the occurrence this disease over a different lifespan.

01:23 is Alzheimer's disease, a developmental It's Alzheimer's disease disorder that usually has

01:30 typical onset in the 20s or as disease, uh an aging person

01:40 And the cases with Alzheimer's is that is much higher onset and occurrence of

01:46 disease if you're 55 and over. , so there's certain neurological disorders that

01:54 manifest themselves early in life, may in the first few days of

02:00 even there are other neurological disorders that and unfold themselves Into early Adulthood and

02:10 20s and 30s and Alzheimer's disease is dementia and alzheimer's dementia is a form

02:18 dementia, it's not a part of aging And Alzheimer's disease is most prevalent

02:27 the population of 55 years and Mhm. So when you think about

02:36 disease, the next thing is you associate certain neurological disorders with symptomology and

02:49 , for example, is a So if you have an infection or

02:56 infection, that's not a symptom, symptom is a headache, it's a

03:02 nose loss of smell, right? with Alzheimer's disease, when you think

03:08 patients that have Alzheimer's disease, what to mind memory loss. So this

03:19 some of the early symptomology that a experiences with Alzheimer's disease. Not the

03:26 symptomology, it's an early symptomology. recommend you take notes on Alzheimer's disease

03:33 also leave some space because we'll come and talk about in the second section

03:39 the course as well. When we about neurotransmitter systems and we'll talk about

03:44 therapy or common medications for Alzheimer's So now memory loss. Disorientation,

03:52 disorientation uh time. Disorientation and then is the early stages of the disease

04:03 what typically happens with many diseases is is called progression, they progress and

04:13 as the disease progresses the symptomology gets and more severe. So if your

04:25 stages early onset of Alzheimer's disease, may be a significant loss of short

04:33 memory a little bit later, there's loss of both short term and long

04:38 memory and then uh severe parts of disease. When it progresses to the

04:46 stages of the disease, you have neuro degeneration in the brain that leads

04:54 essentially your brain not being capable of care of your body leading to

05:01 So many different symptoms along the way the progression of this disease right

05:10 So these are some of the important that we're discussing right the occurrence or

05:16 it is likely that people have Alzheimer's . We're talking about the onset of

05:23 disease 55 plus, we're talking about symptoms. So on good notes to

05:33 progression of the disease into more advanced more severe stages and that the severe

05:40 of the disease, you have a pathological hallmarks of Alzheimer's disease. And

05:47 particular on a cellular level inside the you have formation of neuro february

05:58 We just talked about cyber skeletal elements those neural february tangles inside the south

06:04 actually start interfering with the cell transport external transport and also with the normal

06:13 of the south. In general So we talked about the fact how

06:18 have these micro tubular highways and how have the site of skeletal elements involved

06:24 the transport involved in the support of structure involved in the plasticity and rearrangements

06:31 Nous rearrangements in the structure. So the cells and outside the cells.

06:39 hallmark of cellular Alzheimer's disease pathology. formation of amyloid plaques also called beta

06:48 plaques. Also called senile plaques or plaques sometimes. But these are abnormal

06:58 of a protein that gets cleaved off membrane. Amyloid precursor protein and aggregation

07:09 forms these amyloid plaques that become calcified they're on the outside of the cells

07:16 they're also very dangerous to function normal of neurons. They can move and

07:23 so they're not stationary. And typically Alzheimer's disease there is occurrence of these

07:32 in certain areas of the brain such the hippocampus that we'll talk about later

07:37 hippocampus is a structure that is involved memory and semantic memory or storytelling

07:44 So these plaques can migrate throughout the . They can be located in many

07:51 locations and as they become located closer closer to neurons and start interfering with

08:00 ax on and the ability of neurons produce action potentials reliable. So they

08:07 interfering basically in communication, affecting the between different generals. This is the

08:17 level on the south and south This is the macroscopic level of gross

08:27 uh changes that you would see as compare severe Alzheimer's brave to a healthy

08:37 here and what is happening is there a significant neuro degeneration, there is

08:47 of neurons. There is a significant of the gray matter in particular and

08:54 overall decrease in the volume and overall of the whole cerebrum. So this

09:03 on a macroscopic level. And uh would observe the plaques and you would

09:12 such severe anatomical changes postmortem. Some these you would be able to observe

09:20 as a person is having advanced stages Alzheimer's disease. But quite often there's

09:27 comparison to what the person's brain looked 15 years ago, 10 years

09:33 before the onset of the disease. , okay, so this is all

09:39 things we're not talking today about the will come back and talk about neurotransmitter

09:45 in particular settle coding that's involved in disease and that's affected the most.

09:52 we'll talk about the medications that are used to treat Alzheimer's disease.

09:59 so this I'm gonna share with you this afternoon the slide is going to

10:03 incorporated in the class material. So just forgot to share the extension and

10:10 go back to swat's here. So what are some of the other

10:25 that are different about neurons that have grads and they have them exposed and

10:29 about? They have axons. Axons collaterals axons where the action potential is

10:37 to be produced. This axon is to be my eliminated. If the

10:43 terminal, you'll have a lot of , you'll have the vesicles that are

10:47 with the neurotransmitters and located what we in the active zones, pre synaptic

10:52 they will release the neurotransmitter in the collapse and the boston optical. You

10:58 post synaptic done right here and what call post synaptic densities of post synaptic

11:04 that will be interacting with these Liggins these chemicals that are being released from

11:10 vesicles pre synaptic aly. So uh axons themselves apart from producing the action

11:23 , they also are involved in acts plasma transport. And there are two

11:28 of transport. There's a slow transport there's fast acts of plasma transport.

11:35 under slow transport have tied up axon the early days when people were able

11:42 finally isolate little microscope and you can do it with the naked eye

11:49 Giant axon, it's about one millimeter diameter. They would actually take a

11:55 like a piece of string and they tie around the axon, they would

12:02 the dye and then tie it around axon and they would monitor how long

12:07 it take for this guy to travel the location of the injection all the

12:12 to the distance across the axon. this is tied up axon. They

12:18 the slugs of plasma transport was discovered that which is about 1 to 10

12:23 a day. Some actions can be , depends where they are located but

12:28 can be on the order of sometimes tens of centimeters and lights or

12:33 longer. We also have fast ectoplasmic and fast ectoplasmic transport was demonstrated using

12:42 labeled click assets and the speed of is 1000 a day. So 10

12:53 a centimeter Alright and 1000. I it's a meter, so it's a

13:03 a day. And as we talked micro tubules serving sort of as the

13:09 for this transport. You need to the delivery mechanisms that you need to

13:17 like delivery trucks that right along these . And so these are the motors

13:25 that will carry information in the interrogated interrogators from the soma into the

13:32 And there's another um motor protein die that will be responsible for carrying different

13:44 in the retrograde direction which is from periphery and into this home.

13:51 so we have both kinds of It would be really bad if you

13:57 only one way a highway that had direction from here into uh into Galvis

14:04 and back. Although maybe not so . But you know, so it's

14:09 it's a bidirectional transportation and this kind a transport can be taken advantage off

14:19 you want to trace the connectivity So, so far we talked about

14:25 stains of the dies for neurons. talked about the Golgi stain which was

14:32 for neurons and only a fraction of to cup Golgi stain and revealed all

14:37 the precise morphology of those neurons that taken up Golgi stain. We talked

14:43 missile stain. The missile stain. said it stained all of the um

14:49 neurons and glial cells but did not the precise anatomy or morphology of the

14:56 but rather the cider architectural arrangements of different cell populations. Right? And

15:03 so this is the individual cells. we also want to know how different

15:10 of neurons and how from the periphery different parts of the C.

15:14 S. We have connections. And way to do that is to take

15:20 of these anterograde and retrograde transport that have and use tracers. So there's

15:29 tracers that are mentioned here. There's Peroxide Days which is a chemical,

15:36 herpes virus and rabies virus which are . If you look at this diagram

15:42 shows that you can take horseradish peroxide it's like a diet. You can

15:47 it and let's say you're interested to what neurons are contacting this particular patch

15:55 the brain for this particular patch of muscle with this particular patch of the

16:00 . So you will inject your dye this particular patch let's say of the

16:07 . And then using in this case transport which is from the periphery into

16:14 Omagh's you would have in this case days later a very nice steam from

16:22 area to which you injected the tracer where that trace of travels into the

16:29 . So now you know that it's particular neuronal network that is connected.

16:36 accents of this network are located here nerve endings because it's the retrograde

16:43 So it gets picked up by the and retrograde transported into the summit.

16:49 that's quite important if you want to the connectivity between different neuronal populations.

16:57 I and as I said from periphery uh periphery into the cns. Some

17:05 the viruses are also capable of retrograde like herpes and rabies viruses. And

17:13 can be used for scientific scientific tools labeling for tracing and revealing connectivity in

17:20 brain. Some of the viruses that talk later. And of course when

17:24 talk about some out of sensitive core we will talk about herpes simplex virus

17:32 that is the virus that's capable of . It's capable of interrogate and retrograde

17:39 at different times during its lifespan of virus. So we'll come back and

17:47 about this a little bit more. these are useful tools if you want

17:51 demonstrate a specific connectivity, trace the connectivity between different parts of the brain

17:58 the peripheral veins in the brain. , so we also know that neurons

18:07 endowed with this unique anatomy of having only really complex branches and branches and

18:15 but on the down drives having really arrangements of the great its spine.

18:21 talked about the fact that these dendritic are the points of contact and this

18:27 pre synaptic south. This is the synaptic tax on with the red vesicles

18:32 with neurotransmitter chemicals. And this is synaptic densities of the dem drive.

18:38 this is Ridic spine has here mitochondria and has a smooth into plasma particular

18:46 stores. Uh and so they come different shapes but they do have a

18:53 arrangement on the dendrites. And as talked about the project sponsor the most

19:00 elements. So when you think about of skeletal rearrangements, rearrangements in the

19:06 of the membrane, the fluid mosaic of the membrane being migrated into by

19:13 proteins or different proteins inserted into the membrane. So as you strengthen the

19:21 between the pre synaptic and the possum south. This synapse difficulty strengthens and

19:27 may even grow larger. If there no communication between these neurons, this

19:36 neuron then the spine may eventually actually in size and its effectivity or its

19:44 is not not going to be as . So you can potentially eight.

19:48 spines you can have better efficacy at pre synaptic possum communication or you can

19:55 the spines which is called depression of in this pre synaptic synaptic communication.

20:04 as we're born we actually have a more synaptic connectivity and we have a

20:10 more synapses than we end up having we are adults who were developed

20:16 everything is connected to everything as our are developing and as we're exposed to

20:25 environmental sensory cues and undergo certain genetic for the development and assembly of the

20:35 nervous system. As all of this . The dendritic spines are being

20:43 meaning that you are losing synopsis is you're born with a lot more synopsis

20:48 you end up when you're adult. this connectivity in the developing young brains

20:54 quite non specific. Like I everything is connected to everything, but

20:57 don't want that in the brain and don't have that in the adult

21:01 So we have specific structures connected to specific structures responsible for specific functions.

21:09 these are the most plastic elements. highest levels of plasticity will be found

21:15 intervening spines. If you're learning new , you're strengthening existing good expanse of

21:22 new ones, developing new synaptic connections the expense of maybe some older

21:29 Because we have finite amount of information space in the brain that we can

21:35 and have. Uh Now this process plasticity and anatomical and functional rearrangements are

21:52 dependent processes. So that's why we it activity and environment dependent plasticity.

22:01 it also is dependent on the genetics normal genetic code for the development

22:10 These dendritic spines because they have they have scr right there and they

22:16 polarized. So more complex systems, is somewhat biochemically independence functionally biochemical

22:25 small units that can do a especially post translation locally at the level

22:32 the spine. Not even the dendritic or the selma. Okay, so

22:39 second uh disease that we're going to about today is actually related to what

22:49 talking about the dendritic spine structure. disease is called fragile X. Fragile

23:03 falls under autism spectrum disorders. So are multiple disorders, multiple symptoms that

23:21 essentially classified under this general umbrella. or less of autism spectrum disorders.

23:30 , fragile acts and autism. Uh talking fragile X and neurological disorder.

23:39 talked about Alzheimer's disease and I asked , well, what do you know

23:43 Alzheimer's disease? Memory loss and aging . When you think about autism,

23:51 you think about aging population? Do think about middle aged people? Do

23:56 think about developing Children? So, Children and that would be the most

24:03 onset or when that disease starts manage itself outwardly with the symptomology ease of

24:12 disease. In this case, we're going to talk about the symptomology as

24:17 for autism or fragile. Actually going talk about this particular cellular mechanism fragile

24:24 as a genetic disorder. So, didn't talk about the causes of Alzheimer's

24:32 , but the cause of fragile life a genetic cause it's linked to the

24:38 chromosome where it has a fragile It occurs both in developing girls and

24:49 boys, but it is more severe boys than girls. There is uh

24:58 outward appearance of this disease where Children have abnormally long faces and ears and

25:09 they may have also a smile. they're they're, you know, they

25:14 certain outward facial features that indicate fragile . But our main purpose of highlighting

25:23 X. To talk about the fact fragile X is a mental representation,

25:33 X is a mental reservation. And of the cellular anatomical features that you

25:40 seem fragile acts as well as an models of fragile acts that affect the

25:46 gene. We know it's called the gene. This gene impairment in that

25:55 will cause the abnormal spine monogamy. you can see that compared to then

26:03 from a normal in front, which more or less uniform density distribution of

26:10 spines and the types of the shapes the sponsor we already discussed than study

26:16 white quality. This dendrite now is spines and large swats of this stand

26:26 process All of the spine seem to having one shape only. Then all

26:33 them seem to be really long. what that does is your learning is

26:40 affects the synaptic connectivity and that affects communication between neurons. Therefore it affects

26:47 learning and re leads to learning disabilities mental degradation as well. Now,

26:55 that have fragile acts besides having the , which is a symptom right?

27:05 would also quite often have epilepsy and . So Children that have fragile

27:15 why alpha will have epilepsy. What that? Epilepsy is another neurological disorder

27:28 manifests itself in seizures, these are I call electrical storms in the brain

27:38 have many different ways that they can themselves. The motor component, tonic

27:44 , no motor component, emotional component so on. The number. When

27:48 talked about Canadians gauge and we talked temporal lobe and we said about how

27:54 are certain areas of the brain that involved in emotional processing and on the

28:00 . I had micro stimulation and I temporal lobe epilepsy with micro stimulation.

28:06 said if you stimulate certain parts of brain around the temporal lobe you will

28:10 a certain emotional response and people that epilepsy and have that particular part of

28:16 brain generating seizures. They will also a very strong emotional response. So

28:22 different ways in which seizures manifest And we're gonna talk about epilepsy later

28:27 this course, actually in greater So what is epilepsy have to do

28:32 fragile X is a is also a question. Well, you have neuro

28:41 , you having proper connectivity and neurons it didn't take spines that abnormal you

28:48 generating seizures and epilepsy becomes a co . Oh morbidity with this co

29:03 It's something that can kill you. yes, fragile X and mental renovation

29:12 result in a shorter lifespan because of neurological disorder. If you develop.

29:20 not all Children will have seizures and collapsing. About a third of all

29:25 the Children will have seizures in Asi that half fragile acts. But

29:30 you develop seizures in epilepsy that becomes morbidity independently of the dendritic spine

29:41 their connectivity and mental reputation independently of . Now you have another disease process

29:49 is linked to your first disease and disease manifesting in seizures is also causing

29:56 neural degeneration and it essentially is doing it's has the potential to kill you

30:04 . Okay, so your lifespan, you have one serious for mobility too

30:11 , it could be other things are related to the brain. For

30:16 failure of some organs that are related the medications that somebody is taking for

30:22 years and chemicals that lead to another . That basically, now if you

30:29 23 comorbidities, they can all lead a shorter lifespan. Now, if

30:38 look at this diagram here, this a neuron and everywhere you're seeing green

30:44 these green pancakes, these are glutamate . So these are excitatory glutamate synopsis

30:52 you can see that a single as we discussed in half thousands,

30:57 even hundreds of thousands of synapses on single unit. And all of these

31:03 publications that are shown in orange, standing for Gaba receptor, the Gaba

31:11 is gabba synapses which are inhibitory So in other words, out of

31:20 thousands of dendritic spines, a lot them are going to be excitatory,

31:27 lot of them are going to be neurons have to compute that information that

31:34 in on the barrages of tens of of thousands of active synapses that are

31:42 excitatory de polarize. The cell will to make the cell fired action potential

31:47 communicate that information to the other interconnected and these inhibitory cells that are going

31:54 release gap that are going to hyper these neurons and we'll try to keep

31:59 away from producing an action potential and information. So now this neuron will

32:06 to integrate this information within milliseconds and is excited enough producer action potential.

32:14 quite often what happens when you have connectivity in this case? It's a

32:21 cause uh and you have abnormal formation dendritic spines. Of course it leads

32:29 learning and mental disabilities, but in it also causes an imbalance between excitation

32:38 inhibition. Quite often excitation takes over there isn't enough inhibition. And when

32:46 scale tells stored excitation, the person more likely to start having seizures and

32:55 epilepsy as a co morbidity in the . So what are some of the

33:01 questions about this fragile likes is an spectrum disorder is a mental retardation developmental

33:10 ? It has co morbidity quite often epilepsy and seizures. It manifests itself

33:16 the cellular level as the spine abnormality we're seeing here in this diagram.

33:28 in general neurons will have four functional . They will have an input

33:34 They will have the integrative component to . Yeah in part in part the

33:49 complex the processes, the more complex the native trees are, the more

33:54 you will have more extensive, the likely you will have more synapses.

33:59 see that in in a few slides completed themselves. So now this is

34:06 integrated region. So the soma. whatever inputs the neurons receive they can

34:12 inputs on the soma. They can . Most of the inputs will come

34:15 on the dendrites and spines, neuron integrate that information. The soma and

34:21 initial segment will produce action and then electricity will be generated and will be

34:30 down the axon which is my And then this axon can communicate information

34:37 another neuron and can contact the muscle or even the capillary. So this

34:44 the output region and this is the terminals where you have the neurotransmitter

34:52 Now as you can see that some the south actually don't have the rights

34:57 have to axons. This is a neuron of the dorsal root ganglion of

35:04 spinal cord that has a peripheral axon goes into the skin piece of the

35:11 for information that sends that information into selma selma integrates it and then the

35:18 axon will send information into the spinal proper to excite the motor mirror.

35:25 ? So there are variations. But are four functional regions. Now if

35:34 talking about excitation and inhibition then you roughly subdivide the brain into excitatory neurons

35:42 inhibiting them. And what will unravel the next half an hour to an

35:50 is the fact that there is a of different subtypes of these neurons.

35:55 have maybe 150 different subtypes of We're gonna study a few of

36:02 We have maybe six are so Some types of glial cells and we'll

36:09 about most of their functions too. how can we tell one subtype subtype

36:18 from subtype 57. How did we that? They're all different subtypes.

36:26 do they have to be in order be different? Do they have to

36:31 look differently? They have to live different places or it's altogether their

36:36 the connectivity the excitability. Were they to inhibitory with their projection neurons or

36:42 they're staying locally in the network. we have divisions or classifications of neurons

36:52 are based um morphology purely. You stay in many different south and you

36:58 see that a lot of invertebrate neurons be you know Poland it means to

37:03 one pole in this case is just north pole in this case it's a

37:07 South to dendrite axon and then it so it's invertebrates and we're not gonna

37:13 the cells much bipolar cell this is cell we're going to look at in

37:19 retina in the retinal serving and bipolar has two poles, the north pole

37:26 the south pole, the north That has a done drive and the

37:29 pole. It has an accent. you have pseudo unit polar selves and

37:35 unit polar cells. Ah This peripheral and the central accent that we talked

37:43 . This is the dorsal root ganglion , the sensory neuron that projects into

37:48 spinal cord. And then we have variety of multipolar cells. That means

37:57 south have the north pole, the pole, northeast, northwest,

38:02 southwest and everything in between multiple poles the processes and branching that goes all

38:10 Now. This may answer the question you had earlier Recent neurons, motor

38:17 of the spinal cord that have about synapses. But these cells which are

38:24 into the cells of the cerebellum, little structure in the back of the

38:30 , wow, it looks like it bushy Tree and it has really complex

38:40 and rearrangements of these processes. And cells can have up 250,000 synapses.

38:49 the more extensive uh The processes have really increase the more likely there are

38:57 synapses that are being born in those cells in the middle. We have

39:04 parameter cell of the hippocampus that we're come back and talk about the cell

39:11 later in just a few minutes. it's called the parameter sound because it

39:19 the look of the pyramid. It a base with the basil Denver

39:26 it has the top or the So off the apex of the cell

39:33 you have the abaco Denver ride and the base you also have the axon

39:38 sends out. These are parameter We'll discuss this later today as

39:45 Now some of the neurons are spiny others our spine. So that means

39:54 in every science and the neuroscience or to all of the rules. So

39:58 we're talking about the unique features of of having the spines, some neurons

40:03 have spines um there's other exceptions to rules as we're learning. Especially as

40:10 learning about the classification of bearings. me. Oh well, sponsors only

40:20 side of the synaptic connectivity. They form synopsis on the soma. As

40:26 can form synopsis directly in the dendritic . They can even form synopsis on

40:32 accidents in some rare occasions. So the most part, the dendritic spines

40:38 be the most common side of synaptic between two selves. Three synoptic

40:45 Okay, so this kind of explanation not sufficient enough for us to,

40:54 boy to derive 150 different subtypes of . We need a lot more information

41:04 order to sub classify the cells further out really press hard. So some

41:19 these cells are what we call projection . So the parameter cells excited for

41:27 cells and that is difficult that these gonna be excited for parameter cells.

41:33 projection neurons that means that they are in some part of the brain and

41:39 going to project into the other part the brain. So parameter cells will

41:47 this information Between different structures. That's they're called projection sells the project from

41:55 area to another area. And as standard rule the excitatory projection cells.

42:03 most of the projection cells excitatory parameter are excitatory cells. It needs to

42:10 Ludin eight. Then there are a of cells that stay locally within these

42:21 and they target each other or they parameter cells and they communicate with each

42:30 but their axons don't exit out of network. So there refer to inter

42:38 a lot of times local into For the most part these local inter

42:46 are inhibitory cells and that means that are releasing Gabba and but they're doing

42:59 locally and the excitatory cells are projecting . Excitatory cells also can talk to

43:07 other within these networks so they can locally excitatory cells but they will project

43:14 information long distances into the adjacent neuronal . This is the distinction between projection

43:23 and local inter neurons based on connectivity on excitability glutamate excitatory cell gaba,

43:31 inhibitory cell And then sell specific We all know that a slightly different

43:39 of genes is expressed by these what call 150 different subtypes of cells.

43:44 so we need to utilize techniques such immuno histology and history chemistry in order

43:51 precisely reveal a specific subtype of that . Some cells will have neurotransmitters such

44:00 Gaba and glutamate. Other selves will be releasing other neurotransmitters such as acetylcholine

44:07 dopamine. They also can co express co release neuro peptides. And we'll

44:13 about this in a little bit as . Maybe next lecture. Most

44:19 neurons can produce action potentials. And finally in 1939 there was a first

44:27 recording of the action potential. Uh was equipment that was circuits that were

44:34 enough and the silla scope was fast that was actually concurred with some of

44:38 engineering development and the military and particularly naval engineering. And so the fastest

44:44 were not able to pick up the potentials because these action potentials produced by

44:50 are only 1 to 2 milliseconds in . So you need it really fast

44:55 in order to pick it up really equipment in order to display this on

44:58 screen and then take a Polaroid shop then send it to a journal with

45:04 description. Uh so now we realize what's really important and when we look

45:10 these different subtypes of the cells, not only their anatomy that is

45:15 it's not only where they're projecting or their locating in the network and whether

45:21 excited or inhibitory cells. But it's very important the frequency and the pattern

45:28 the action potential. So these are potentials here. Each one of these

45:32 and you can see that the cell here on the left, produces a

45:38 fast sequence of action potential. It's the exact same stimulus as the cell

45:44 the right, but to sell on right response very differently to the same

45:51 . And it never produces a very frequency of firing. So once we

45:56 , not only doing, you individual cell action potential recordings, but

46:01 capable of patching or recording from multiple neurons in the same area. We

46:10 that these neurons speak the same language is action potential, electrical electrochemical

46:19 But they all have slightly different And this is another distinguishing feature or

46:28 different subtypes of south. So before get to the firing pattern of the

46:35 potentials, we must return to this here and this slide uh may seem

46:48 . This articles are posted in your supporting lecture documents. So if you

46:54 to read the figure legend for this figure, you can It's somewhat dated

47:04 back to 2008. But the principle where, what we're about to discuss

47:13 the same. Let's start from talking what we're looking at is we're looking

47:20 the campus just we're looking at one of this hippocampus. It's a small

47:30 both sides of the brain. Hippocampus a hippopotamus but campus hippo campus mhm

47:45 is responsible for semantic memories, facts, stories, interpretations,

47:59 So in fact when you're talking about names of people and remembering short term

48:08 memories, hippocampus is involved and hippocampus be affected by diseases like alzheimer's

48:18 That's where you have a memory loss one of the symptoms of Alzheimer's disease

48:24 the campus is also a part of we call the limbic system. So

48:30 is not only involved in the memory and recall of that memory but it's

48:37 involved in the emotional information processing and memories. As you know a lot

48:45 crimes, memories are tied to a emotion and in fact the greater than

48:51 sometimes the better is the memory or it is to forget. Ah So

49:02 two are tied together. The campus also referred to as our key

49:11 Are she core tax. Our key an abbreviation for archaic its ancient cortex

49:24 the campus is ancient because it has three cellular layers on the top

49:33 It has stratum Ready autumn straddle stance layer, bottom layer in the middle

49:40 banned here. It has straddled from dollar Paranzino player and stratum.

49:48 So it's three predominantly three layered structure that's what our key cortex because neocortex

49:58 typically what you refer to cerebral Neocortex Is a six layer structure and

50:06 stands for new. The neocortex is latest and the greatest in the human

50:14 cognitive conscious and motor development skills and is three layered structure. So I

50:23 hippocampus is trying to become a six neocortex slow and it will sell maybe

50:31 some years. Who knows? So we were to take the hippocampus and

50:37 were to ask a question. Other cells in hippocampus are the excitatory cells

50:44 hippocampus. Uh So you were to a question what types of cells

50:54 We talked about the two major Excitatory versus inhibitory cells. Right.

51:00 we know that excitatory cells will express and inhibit their selves will express

51:07 So you were sustained for glutamate, to 90 of the south and the

51:17 are going to stain for glutamate which excitatory and the remainder 10 - 20%

51:26 going to stay in for Gavin. you stand for these glutamate cells,

51:32 want to ask the question, are different glutamate cells, how many different

51:38 of cells, how many different subtypes excited for yourself. And so then

51:45 will utilize dives, you will utilize like Golgi stain in particular because Golgi

51:53 reveals the precise anatomy of the cell of that cell. So Golgi stain

51:59 picked up by the cell, it reveal that it's so much located in

52:04 layer and it turns out that the of all of these excited cells are

52:09 densely populating this parameter way So out those 80, of all of the

52:16 cells in the campus, most of 80 90% actually live in this pyramidal

52:24 . There's so much live in But if you use the stand you

52:29 see that there's a soma here from dollar layer. There's another phenomenal cell

52:34 and orients layer and there's another one radiology. But then you look at

52:39 morphology and you say there's nothing different their morphology. They have a pickle

52:45 rides, they have basil done rides their projection cells So their axles are

52:50 to come out of this network are to come out of this local

52:55 One network from the parameter cells. it's going to project into other parts

53:00 the brain. Okay. Because these excitatory projections for our little selves communicate

53:08 between each other but also into the and sometimes far away neuron all networks

53:13 which they connect to. So you that morphological and you say you know

53:19 ? I can't really tell the The only difference I would say is

53:23 it's the same looking karam. It'll except a very small number of them

53:29 in the ready atom layer. That's living ready atom layer. A very

53:34 number of parameters sell so much 20,000 . But I really if I do

53:41 any other morphological description is the same of cells. And so I mentioned

53:47 that different neurons and different cells in body and different subtypes of cells in

53:52 body. Different subtypes of neurons in brain will express a slightly different subset

54:00 genes, a slightly different variation. may have inter cellular markers that others

54:07 have. And so these intracellular markers not just a marker. Oh the

54:12 has something, they're typically meaning that have a different function. So some

54:19 cells and most of them that live the valley layer will stay positive for

54:25 which is called bending and Calvin them the calcium binding 30. So they

54:33 a calcium binding protein in the But these don't, that means that

54:37 going to buffer and regulate calcium functions the South using this Calvin gene protein

54:44 a different way from these neurons. in fact these neurons will all speak

54:51 same dialect, the same frequencies and of action potentials. So the only

54:57 that we can really distinguish what turns to be two subtypes functionally in three

55:04 that we look at the location of layers with Farrah Minal excitatory projection cells

55:10 pretty boring. They have called indian they don't have called indian and it's

55:15 just two or three subtypes of that morphological and distinguishable action potential pattern dialect

55:24 indistinguishable. Very uh one distinguishing feature called in some cells express others,

55:33 know and that makes them a different of the excited projections. So So

55:40 next question to ask logically in this or in the study, what about

55:46 Gabba neurons? These Gabba neurons comprise 10-20% of all of the cells in

55:54 Hippocampus and in this area of the here. But are they all the

56:01 subtype of inhibit third south. And , you would use the stains,

56:07 try to reveal the location of the and the morphology. And when you

56:13 near 1, 23 all the way 21. These are all different subtypes

56:22 the inhibitory gaba cells that are local into neurons. That means that they

56:32 communicate within this network here. But don't have little cells of the axles

56:38 project into other areas into neurons do . And how come there's such a

56:45 variety of these inhibitory cells and it out that if you say them,

56:51 can very clearly tell the difference between of them the location of the So

56:56 , you know, opera versus versus land then rights that are horizontal with

57:06 growing vertically versus dendrite the stick lines are vertical and axles that are also

57:15 vertically. So morphological li they're You already can sell the differences.

57:25 what are some of the distinguishing factors . There's so much location. Then

57:31 finally these yellow cups here. These cups indicate where these excited with these

57:38 ourselves are going to target the So the cups are near pyramidal

57:45 That means they're targeting parameters somewhere. the soldiers of these parameter cells and

57:52 neurons that are located in the parameter in the south for example. Number

57:59 . The cups, the yellow cups target the very ethical gender. So

58:06 have very clear distinct morphology. The of the Selma's very distinct morphology in

58:15 dendrites, lateral horizontal versus vertical and distinct projections on how they talking.

58:27 they contact onto the parameter cells on apex, on the so hmas or

58:34 . The soma is even on the . But what is the difference between

58:40 number two and film and before morphological look identical to me. They have

58:50 So Mazarin, the parameter layer number . Number four. The den drives

58:55 vertically projecting. Number two. Number the axles or the synapses that their

59:02 phenomenal cells are in the same region the abdominal cells. And the only

59:09 that you would distinguish between these two of cells is both of them are

59:14 called basket cells. And some of South. Number two is positive for

59:19 specific cellular market called for monument. those are four is having another different

59:28 markers such as C. C. . Which stands for calling. So

59:34 they're actually two different subjects themselves. if you're submitting a paper and you

59:41 performed any study to the cell. specific study let's say you're recording electro

59:50 activity and you submitted your paper and said my cells are recorded from where

59:58 cells in the hippocampus and the reviewers no thank you. Not for our

60:04 . Send it someplace cells. Because it's too broad, it's too

60:10 when you look at this very complex where the complexity actually stems from the

60:17 and functional variety of the inhibitory If you look at this and simply

60:23 I recorded from inhibitory cells, that's enough information. So in order to

60:32 your reviewers that I recorded from number cell and from the parameter all

60:39 What you have to do is you to prove them, you have to

60:44 different frequencies of action potential. So have to show them these cells actually

60:49 two different dialects. You have to the morphology and say you know what

60:55 is the cell that's located and Orients and projected axons all the way to

61:02 in this particular cell also has a sound marker in this case Samata statin

61:11 it actually is some number 71 of favorite ones neuron that is called it

61:25 from orients and it goes to all so this this is this is the

61:36 that we recorded from but that's what takes to to specify what specific subtype

61:43 neuron you're recording too. Especially if recording from inhibit ourselves. It's not

61:47 big of a challenge if you're recording excited for ourselves because we have to

61:52 stay for Calvin then and prove that cell you recorded from Calvin and positive

61:57 not. You have to reveal the , the projections as self specific

62:03 all of it. Yes. So more complicated than no. Uh very

62:15 question. This circuit in the We're going to also look at the

62:21 cortical circuits which are six layer circuits they're more complex too. This is

62:28 what we call canonical, which means you will find these arrangements of local

62:36 inter neurons that have a variety of subtypes targeting these excited projection sells locally

62:45 are projecting excited during information. So from a computational perspective the complexity and

62:57 if the brain comes from the variety the inhibit themselves and their ability to

63:03 different dialects and express different molecules. fact, I wasn't maybe going to

63:09 to the slide but maybe we can you were for example to target neocortex

63:17 you were just to record from the of the neocortex here, let's say

63:21 centimeter from different neurons you will soon out that these different neurons, they

63:27 the same input. But this is output that they produce for the action

63:32 . So this would be like bursting mm These are very fast firing cells

63:43 earlier. Then you have that stuttering , this one is again continues but

63:58 . This is delayed stuttering so it an input and it thinks about it

64:03 23 seconds and then it goes rubbing a bike. So these are different

64:13 that the cells speak and these different stem from the inhibitor ourselves. So

64:22 think more complex. I think definitely they're more difficult to understand it difficult

64:28 identify a specific subtype of the But also we can process a variety

64:37 different frequencies. Sensory we can have outputs in different frequencies because these inhibitory

64:46 will locally control what the excitatory cells between the networks. So and this

64:58 what we call the dialect of It's the same language, it's the

65:02 action potential. But the pattern and frequency that the cells produce is the

65:07 why they produce different frequencies is because express slightly different subset of genes and

65:15 have different ion channels and therefore different biophysics that allow them to produce either

65:24 , slower, delayed stuttering, continuous patterns of these action potentials.

65:31 cause more damage to the laboratory self which one diamond which will cause us

65:45 damage if you lose inhibit they're excited yourself. I think that I don't

65:53 if you can put it on a . Kind of a two wave it

65:55 you but it is more likely that neurological disorders associated with imbalance. Where

66:06 less of excitation, there's lots of . Um And because if you look

66:19 some of the significant networks, it's 10 to 20% of the self

66:25 So if you lose 1 to 2% 80 to 90% it's not that much

66:32 a loss of function or some But here You're looking at significant potentially

66:39 decline in some balance in the brain between neurons. Uh Yeah, so

66:49 need we need this variety, we these different types of cells to speak

66:55 dialects because we have very complex sensory , bombarding us a different frequency,

67:00 slow, some fast, some some continuous, we have to adapt

67:06 them. Uh and we have to very complex information, writing motor

67:15 playing games, speaking, painting, music, this is a motor

67:21 And so you need again, if you can liken it to music if

67:26 only have cells that can produce one of the action potentials. This rhythm

67:33 none all that means all of the on the radio, you know?

67:41 you can think about that in that as well. Alright, I think

67:45 gonna end here today because after this gonna venture into a little bit more

67:52 electrophysiology and then jump into glia. you have any questions about this hippocampal

67:59 , hang on to them until I'll come back and review that slide

68:03 . We can ask any questions, I'll point out some of the things

68:07 may be important for you to know the exam from that slide. Thank

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