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BIOL 6397 Cell Neuroscience Mo Wed 1-2.30pm - CELLULAR NEURO Lecture 02 Neurons, glia, and Tripartite Synapse
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00:02 this is cellular neuroscience lecture too. reviewed a little bit of a
00:08 we understood how historically our understanding of as electricity conductors and electricity generators came
00:16 in 1780 with Luigi and Giovanni discoveries we also focused on how the 18th
00:26 In the 19th century and onwards, in anybody's studying the brain is really
00:33 about what parts of the brain are for what functions and where they're located
00:39 how they may be interconnected. And had this approach of essentially reading out
00:46 size, angles, operations, curvature in the scalp that they believed represented
00:57 certain innate abilities for certain functions of brain. And so they really tried
01:04 subdivide the brain into different parts that responsible for these different functions with their
01:11 was that they were really doing it reading the shape of the skull rather
01:16 looking really inside the brain. And our understanding of specific localization of the
01:24 functions comes from the loss of clinical studies and and and later experiments
01:34 electrical stimulation of the brain experiments. so we discussed paul Broca and this
01:40 in the brain on the left hemisphere is located close to the motor cortex
01:46 called Broca's area dr broker noticed the to this particular area, so damage
01:52 the brain results in the loss of . In this case it's expressive aphasia
01:58 the ability to produce words. It's to the motor cortex and damage to
02:05 parts of the brain, such as focus area would result in a loss
02:10 function receptive aphasia. Neither one of result in a complete loss of speech
02:21 , but very specific loss of conscious the speech comprehension or speech production
02:29 And so veronica's area is also more related to the, to the temporal
02:35 . We also talked about economic. amnesia, Aphasia is the mildest form
02:40 global aphasia is the most severe form evasion involving extensive, typically damaged um
02:48 loss of complete loss of of speech to understand right here and then there
02:56 parts of the brain that when you damage to them in the case of
03:00 gauge, he had this massive explosive instrument that penetrated through his brain and
03:08 out, took his eye out but also damaged his frontal and prefrontal cortical
03:14 here and that loss of function for was an ability to control himself,
03:22 and loss of memory to its interconnected some of the memory encoding centers.
03:29 he's probably one of the most famous in as far as significant traumatic brain
03:37 . Observable damage, significant damage to brain that's large and extensive yet the
03:47 of function is limited to somewhat of cognitive and executive control functions,
03:55 control functions but all of the other functions, hearing, listening, of
04:02 not seeing in one eye. They're they're all preserving him Now. At
04:06 same time, you could reproduce some the movement activity in the brain or
04:12 of the emotions in the brain or some of the things that different searches
04:18 the brain are responsible using cortical So at the same time In the
04:24 and 19th century 19th century particularly, have a lot of the studies that
04:30 the brain and see what would the is of that stimulation. Of course
04:37 lot of it is animal experiments. also a lot of experiments and debate
04:42 the whole brain is responsible for all the functions or whether different persons,
04:47 brain is responsible for specific functions. debate rages on until the 20th century
04:53 the scientists, Lashley that is cutting large chunks of pigeons brains and he
04:59 believes in this sort of all of brain is responsible for all of the
05:04 . And even before that we discussed if you just look at the brain
05:10 translucent so you really cannot visualize the elements such as neurons in the brain
05:17 . And to do that, you to have a stain. So the
05:21 in the brain is mostly in the And the stain that has discovered at
05:28 end of the 19th century is a standby camellia bulgy and Golgi stain gets
05:36 up by a fraction of neurons in brain. Just want a few percentages
05:42 neurons will pick up this silver nitrate stain. But when the cells pick
05:48 the Golgi stain, all of the such as the dendrites shown here in
05:54 , light brown, and the optical and the basal dendrites and the Soma
06:00 neurons and also in black. The of these neurons and the axon no
06:07 or X. Anno collaterals also very clearly exposed. The Golgi stain
06:13 a great way to delineate the exact morphology, structure or anatomy if you
06:22 have individual neuronal elements which will have shape and will have a different look
06:28 them. And so at that if you look at the brain and
06:33 saw one continuous blog that's kind of cloud of census. She um collection
06:39 billions of these nuclei but enclosed by sheath of plasma membrane. That's what
06:48 theory stands for. And that's what bulgy was proponent on despite the fact
06:55 he discovered, you know, familia is on the left here and here
07:02 the middle picture, you have Ramona how who, as he was drawing
07:10 cells using this camera lucida microscope which allows you to visualize the same
07:17 brain tissue and also through the mirror to draw these circuits that you're
07:24 These are actual drawings from Ramona He was a proponent of neuron doctrine
07:29 argued that neurons are discrete units with own individual cytoplasm and above that he
07:38 that to them rights and the soma be receiving the signals as these arrows
07:44 . And that the axons that are in black would be carrying the signals
07:50 neurons into the adjacent interconnected neurons. also started discussing the concept of
07:59 suggesting that these connections are not set stone, so to speak. You
08:05 forever, but rather a malleable are so that the neurons have the ability
08:14 reshape their connections with other neurons and network and Charles. Shelton on the
08:22 was the person that coin the sterling described this term of synapses. Very
08:31 Place space between two neurons where electrochemical transmission takes place In 1906 Camillo Golgi
08:41 Ramon alcohol except normal price together. they never to land degree uh on
08:48 the brain is one since Ishi um to Golgi or whether it's comprised of
08:55 , discrete neuronal units according to Ramon and many other scientists. But these
09:02 , these detailed drawings are still shown this day. This thinking that harmonica
09:07 had, it was very forward thinking 100 years ahead of his time
09:14 Uh And uh we're still at that , although we had the discovery that
09:22 conduct electricity and learns conduct electricity early . Um but we still don't know
09:32 these neurons and these arrows, the that is being transmitted by these arrows
09:38 an electrical signal. We suspect that we don't know that there are these
09:44 small fast electrical changes to the member the country called action controls, which
09:49 discovered later. The current view and challenge with the 21st century of neuroscience
09:58 that we actually want to be able observe brain activity non invasively. And
10:04 of the techniques for observing brain activity , basically that we will discuss on
10:10 sports are pet or positron emission tomography F. M. R.
10:16 Functional magnetic resonance imaging and these are techniques and these are human brains that
10:22 looking at. And these two functional techniques. Because we'll also discuss how
10:31 imaging. When you're talking about functional , we're talking about function and activity
10:37 these neurons. And so when you're at these red hotspots of these maps
10:43 we call an activity that correlates a function and a this map of activity
10:50 to looking at words and you have primary visual cortex in the occipital lobe
10:55 is engaged and looking at the words these hotspots are active nerves, active
11:03 circuits of interconnected neuronal circuits that are and as neurons are active, they
11:12 oxygen, they need nutrients. And when you look at the functional imaging
11:22 that are non invasive than both pet and FMR eyes are performed non invasively
11:28 the spoils that you travel through and image your brain and three dimensions what
11:36 what this activity indicates indicates consumption. this case it could be glucose consumption
11:44 pet in Madrid for F. R. I imaging it's the blood
11:50 and the delivery of oxygenated blood to region. Because neurons that are
11:55 they will consume oxygen, they will workers. They will swell and so
12:03 will require and will be under much metabolic turnover rates than the areas of
12:10 brain that are not active at the . So these are noninvasive clinical techniques
12:17 are functional imaging techniques and these techniques allow us non invasively to visualize larger
12:26 of the brain to have this really view. There is no resolution of
12:32 single cell in the positron emission there is no resolution of a single
12:37 F. M. R. They usually the pixels of the box
12:42 size that is imaged. It's typically the order of centimeter squared centimeter millimeter
12:54 and maybe down to 100 micrometers. , as you know, the size
13:00 a typical neuron is about 10 And if you want to visualize individual
13:09 and even more. So if you to visualize individual processes of the neurons
13:15 once you zoom in using experimental microscopes experimental imaging techniques that you cannot use
13:24 the hospitals and the clinics, you fluorescent imaging techniques. So you can
13:29 on microscopy, you use other sophisticated developing emerging forms of microscopy, you
13:37 that it's not only the dendrites, in particular these very small protrusions called
13:42 spines that come in different shapes and shape and thin shape and short stubby
13:48 shape. That these dendritic spines are the sites of the synapses which is
13:54 other neurons will contact. And most the connections will be formed are on
14:00 dendrites and dendritic spines. Along Done right. But you cannot visualize
14:05 single synapse, you cannot visualize a spine, You cannot visualize a damn
14:11 or even a single neuron using these imaging techniques. Therefore a lot of
14:18 is happening experimentally in the lab and the ability to go to a single
14:25 level microscopic level two single molecule not a single synonymous with single molecule
14:33 say single neurotransmitter receptor protium going down that single molecule level, going down
14:44 single synapse level which is 100 Spine that gets contacted by another neuronal
14:53 . So understanding at that level you to have experimental techniques and we have
14:57 start merging in this century. The to understand single molecule, single synapse
15:04 . Single neuron behavior with a greater of the overall brain networks and certain
15:11 you can see clinical. And so in at some point, let's say
15:16 20 68 just made up, there might be a super duper scan
15:28 techniques, non invasive which means that don't have to open the skull.
15:36 noninvasive that we'll be able to analyze of it together. All literacy on
15:41 right side. Bottom here on the to spy in some individual synopsis and
15:46 overall activity of the whole network and and really make a lot more sense
15:53 these activity maps that we now see clinical level. But these activity
15:59 as you can see if you're looking words, you'll engage the occipital primary
16:04 cortical areas. If you're listening to you will engage the auditory areas and
16:11 temporal lobe receptive aphasia areas that we've discussed. Bernardus area a lot of
16:18 . Speaking words which will engage Broca's and the primary motor cortex. And
16:25 thinking of words that you can see there are other areas not primary sensor
16:31 , not such as looking or listening speaking motor function to the words.
16:36 thinking about the words that involves other of the brain and has a very
16:42 activity map. So this activity map active neuronal circuits that are interlinked and
16:49 communicating to other neuronal circuits. And of the imaging that you see through
16:55 and through F. M. I. Is through the cortical
16:59 It's quite difficult to reach into deeper . Ical areas of the brain which
17:04 also a good challenge that should be . So uh light microscopy microscopy level
17:12 can have a resolution of 0.4 But the synapse is about 20
17:18 So the synaptic cleft or the space neurons. 20 nanometers Using electron
17:24 you again can visualize these beautiful anatomies you have pasta mathematically it's pasta.
17:31 density where you have a collection of receptor such as glutamate. Post synaptic
17:37 will be located here. There's the spine which also has mitochondria in
17:44 And these boston athlete densities and the side and the red are juxtaposed with
17:49 terminals and these ground structures that you're in red, they represent vesicles or
17:57 vesicles. And as you can see lot of them are located very close
18:01 the release site. So this is pre synaptic external terminal and this is
18:06 postseason attic den driving the dendritic spine the receptors. It's the release of
18:12 chemical and the synapse here and this flat is an absolute collapse and binding
18:19 these chemicals to the receptors in And the post synaptic densities will cause
18:25 deep polarization and change of activity from possum act it sounds so you have
18:30 shapes of the recent applicants post synaptic here as is indicated by these electron
18:38 images and you have very sophisticated microscopes studying different synapses. Dendrite cells of
18:50 resolutions come focal microscopy and they can visualize the release of single Mexico using
19:00 fluorescence techniques. So there's a lot things that will allow experimentally to go
19:06 to the single sina single vesicles, molecule level. But on a clinical
19:12 you're still looking at these overall greater level brain activity maps and interactions that
19:21 recording at much lower resolution. Uh this is an interesting technique that comes
19:30 very handy. And if you read electrophysiology papers or if you're in biomedical
19:37 and you hear about this neuro physiology electrophysiology techniques, so they're recording from
19:44 brain or their reporting from neurons. so how can we report from the
19:50 or how can we report to If you cannot visualize these neurons and
19:55 have to stain them and put it a microscope and a slice and how
20:01 can you record what are some of reporting techniques? So this is an
20:04 vitro recording technique in the dish and brain slides. There are also in
20:11 electrophysiology recording techniques. And the the premise of electrophysiology is that you're placing
20:18 micro electrode and you're placing that micro into single cell. Were you placing
20:25 micro electorate nearby the network ourselves? if you're placing that micro electrode in
20:32 single cell, you're doing either whole For intracellular recordings and most of the
20:38 papers you'll read these days, I probably better than 90% would be using
20:44 cell patch clamp technique. And this an illustration of how this electro physiological
20:51 can be done in the future. the slices wholesale patch crime technique.
20:55 place the slides The 10 slides, is typically about 300 micrometers and thickness
21:03 flies. And it's about maybe a of centimeters and in diameter. And
21:15 it's very, very thin, 300 thin slides and that slides gets illuminated
21:21 white and that light Passes into the which magnifies. So if you have
21:32 have a magnification of a minimum of x. And typically in the lab
21:37 would magnify it up to 140, . And past that life an image
21:45 has been lit up and magnified that that to the side of the nurse
21:52 will pass that image back into the camera here. It's solis iR camera
22:01 with the infrared cameras and this differential contrast microscopy you actually can visualize individual
22:11 . You can visualize their dendrites. larger gun rights and sometimes even axons
22:17 they're quite prominent or you can have really good resolution in the tissue so
22:23 do not need to stay in the . Now you have the ability to
22:27 networks of cells and also individual cells target the cells with micro electors and
22:34 electrical potential activity and record electrical action and action potential patterns using these types
22:42 techniques. Again, you cannot do in human brains. You cannot place
22:49 electorates in single cells as of yet can in humans in pre operative surgical
22:59 , meaning that before the brain Brain surgery is performed. You can
23:04 micro lectures in the brain to record own selectivity and you can actually calculate
23:10 pick up single neuron activity that you in humans perform these kinds of
23:16 And so there's a neuroscience in any science and any emergent new developments and
23:23 have to have a perfect marriage between you have available as experimental tools.
23:31 and would you have available as clinical and obviously experimental tools. We mostly
23:41 to determine basic mechanisms of actions, mechanisms of actions of drugs interactions that
23:49 sell single self synopses. And in clinical view you don't usually just go
23:55 scan your brain just I want to all my brain scan looks when I'm
24:00 about some story versus compared another It is typically a clinical situation meaning
24:08 abnormality or something that you're imaging and brands of being able to understand all
24:15 these levels from micro to the big level. It is very important um
24:21 this neuroscience field and anything that's related biomedical engineering or ah anything of that
24:30 . Now the tripartite synapse and why I keep emphasizing this tripartite synapses that
24:38 for a long time, you know thought that most of the action was
24:43 between neurons and the glial cells in case you have astra side astra civic
24:50 shown here. Astro side is the of glial cells we ourselves are actually
24:58 numerous in the brain and europe's but yourself would offer a long time to
25:07 a supportive role at the center in communication between the pre synaptic neuron
25:12 We just discussed the release of He and the synaptic cleft in the
25:16 synaptic response binding of that visible to receptors in the post synaptic response.
25:24 while it actually turns out that leah very actively involved in this chemical neural
25:36 cross. But the more we learn the next couple of lectures, the
25:40 you understand that we in particular is here. Bluetooth transmitters leah transmitter.
25:50 there are neurotransmitters under glial transmitters that affect neuron Between excitatory neurons in the
25:58 . You have two major subtypes of . Excitatory neurons and then hit the
26:03 excited to go somewhere else at least there. And when they release that
26:08 glutamate it will de polarize or excited matter itself if this priest are not
26:16 neuron has an inhibitory chemical neurotransmitter gaba neuron is inhibitory and release of that
26:26 neurotransmitter chemical and binding of it to post synaptic receptors will inhibit or hyper
26:32 activity of the pasta map itself and as their intricately involved in the
26:39 So that's why it's referred to as synapse, part one neuron one part
26:44 neuron to part three Williams and it's just supportive role. It's shown that
26:50 actually uses calcium for signaling And glia has shown here in particular with glutamate
26:59 obliterate and imports glutamate molecules and then synthesizes them and really leases them for
27:07 to be reused again. So in ways believe it controls these chemical communication
27:15 the amount of chemicals that are available the great synaptic neurons and with their
27:22 guido transmitters, they can also affect synaptic neurons. And so that's why
27:27 referred to tripartite synapse. And I wanted to to emphasize that early on
27:34 we will learn about neurons and how signal and communicate and how neural networks
27:40 also will be herding about leah. there's gonna be a recurrent theme of
27:45 tripartite sooner. Now when we look this kind of signaling that's very specific
27:54 . We uh right here then you glutamate which is excited during the transmitter
28:00 Gaba, which is an inhibitor in and both glutamate and Gaba produced locally
28:07 these neurons and are released by the the by the by the axons and
28:14 cycle back locally either back into this optic terminal back through the glial
28:22 But it is all happening locally and have this tripartite synapse arrangements all over
28:29 brain. So neurons will be communicating neurons with glutamate and Gaba all over
28:35 brain. And but we will also about other forms of neurotransmitters that we
28:43 neuro modulators. And these are typically means that we call and refer to
28:50 norepinephrine or serotonin but also we'll be about acetylcholine and some other molecules in
28:58 sport. And so now you have very localized signaling in the brain and
29:04 stripe part synapse localized meaning that you these neurotransmitters themselves and you locally replenish
29:12 in these synopses. But there are that actually get produced and just very
29:19 nuclei in the brain. So like that are glutamate till the gabba producing
29:26 will find all over the cortex, over and sub cortical structures all over
29:31 cerebellum. These other molecules such as africa such as serotonin, they're produced
29:40 very specific nuclei in the brain. recall that nucleus in the brain is
29:46 collection of South that is responsible for or the same type of functions in
29:52 case locust, cyril ius the blue is responsible for producing norepinephrine and there's
30:00 cells in the cortex that will be and producing norepinephrine unlike glutamate unlike
30:10 And so this norepinephrine will then gets throughout the cortex almost like a sprinkler
30:17 system through the cerebellum and into the cord just from this one nucleus,
30:24 civilians and no other South. No sarcomas in the brain synthesize. And
30:31 are the external outputs that come out the soma of the south of produce
30:37 Aurelius and the local civilians nucleus in brain step serotonin a very important uh
30:46 neuro modulator in the brain was produced rat nuclei and you have wrapping nuclei
30:52 purple that the so mama's that are in news nuclei will sound sort of
30:58 into the cortical areas and cerebellum and rapid nuclei located and brain stamp in
31:07 . We'll send the serotonin into the cord into the periphery. And so
31:14 have a collection of different molecules tuxedo . How about freedom, histamine,
31:23 , acetylcholine, norepinephrine and serotonin that very different from glue, dramaturgical signaling
31:32 we're about to discuss for the next or two. All right, so
31:37 keep that in mind that there are tripartite synopses that are located throughout the
31:43 . And then there are other chemicals other neuro modulators that are produced by
31:50 specific collections of neurons throughout the brain . And in this case in the
31:56 basil, forebrain fur seal, Colleen they have their projections or axons distribute
32:04 chemical widely throughout the cortex of balance down in the periphery of the spinal
32:13 . So this concludes this first introductory in this introduction of what is a
32:20 synapse. How we need to think these local interactions and excitation and in
32:27 how leah is involved in that and there are other chemicals in the
32:32 Also. Many chemicals in the brain these other chemicals that are localized but
32:38 sprinkled throughout the brain will ultimately affect of excitation levels of inhibition and modulate
32:46 levels and modulate the computation of the as you learn because each one of
32:52 chemicals, if you may you can of glutinous name is something very
32:58 Plus Gabba is something fast and the . They're also slower processes. Medical
33:06 processes that both Gaba and glutamate turn and these items out of the
33:13 chemicals and processes that are mediated by means that will also influence as fast
33:20 ergic and gather urgent neural transmission. we continue here with neurons And neurons
33:34 comprised only 90-10% of the of the mass and we comprise 90%. So
33:40 lot more real cells are present and why I have this analogy that neurons
33:46 like chips and the chocolate chip cookie glia really in in greek means.
33:53 glue, Lots of glue is the and think about it. You actually
34:00 have a chocolate chip cookie without. know, if you just had the
34:05 , it's just the dough I guess still we could Sprinkle sugar on it
34:11 call it sugar cookies or whatever but not interesting. You know the action
34:16 in chocolate, the chocolate chips. in order to have that you have
34:22 have the supporting cells and it's not supporting cells. They're proactively involved in
34:28 those chips their flavor, so to . And you have billions of neurons
34:35 form trillions of synapses in the brain that have these very sophisticated pathways and
34:42 of inter connectivity, neurons, as described, excited to neurons will synthesize
34:48 release glued to me inhibitory neurons will and release gamma amino bu terry Cassidy
34:55 Gaba both glutamate and gaba amino So the amino acid neuro transmission neurotransmitters
35:05 as I mentioned they're both involved in neural transmission, meaning that when the
35:14 gets the polar hasn't been action potential milliseconds gather with the meat will get
35:21 within a few more milliseconds. Those will travel across the synaptic last and
35:28 will buy into ion a tropic receptors causing a post synaptic effect in the
35:35 of literally deep polarization. In the of gaba hyper polarization through ion a
35:41 receptors within milliseconds. This is the fashionable transmission that we're talking about both
35:50 innate and gobble will also bind to tropic receptors. So these are g
35:56 coupled receptors that are not ion channels to set on activity through metal tropic
36:05 and metal tropic signaling cascades. It's on the order of a few
36:11 It's rather on the order of tens milliseconds delay from when that glutamate er
36:16 were released. So it's slower processes meddle with tropical signaling. Can also
36:23 on slower processes within the cells including upon even the genetic factory and the
36:32 factors and transcription mechanisms within the cell all these other molecules that we were
36:40 about previously. There means with the of acetylcholine. They operate in the
36:49 . N. S. In the through medical tropic signaling through medical tropic
36:55 . The past is through iron Entropic slowest the medical tropics and then there
37:01 slower processes that are mediated by As I indicated Glia uses calcium and
37:08 waves for signaling. And these processes underwater. Hundreds of milliseconds amounts to
37:15 seconds in duration. This is a representation of different subtypes of glia that
37:24 have in the break. We have . We have a little damnedest rights
37:28 we have micro glia. Uh you this append um All cells dependable cells
37:35 the barrier between the cerebral spinal fluid what we call the interstitial space which
37:41 the space in between the cells. so the cerebral spinal fluid constantly gets
37:47 within venture costs and gets fat and with nutrients and all of the goodies
37:53 the interstitial spaces in the brain. the astra sides as you can see
37:59 are not only linked to the synopsis where you talked about in the tripartite
38:03 . That means they're patrolling and influencing activity. Astrocytes are also involved in
38:10 genesis or generation of new synopsis and synaptic plasticity. So by having the
38:17 to control levels of glutamate. These can control the ability for these nimrods
38:23 the critics finds to be plastic astrocytes extend their foot processes onto the micro
38:32 in the brain and are a part what we call the blood brain
38:37 So the goodies that are in the that is entering systematically into the
38:42 They're being patrolled by a barrier that's blood brain barrier and astra sides and
38:48 emptied and have a great role to in what passes through the blood brain
38:53 into the interstitial brain space. Legal sides in the cns are concerned with
39:00 Nation. And so you'll have one defector side that will have many processes
39:06 off of it. And each one these processes will form a single myelin
39:14 . And most of the axons in CMS are Myelin ated and this Myelin
39:20 will provide for insulation so that the can conduct the signals without losing the
39:28 signal from the selma all the way the distal parts of the axons.
39:34 legal tender sides will provide this Myelin in the CMS, michael glial cells
39:40 the fastest the most mobile elements in brain when there is injury in the
39:46 , micro glial cells will actually migrate the side of the injury first by
39:51 their processes and then secondly, physically towards the side of the injury.
39:57 the smallest and most mobile units in brain. Michael guajillo salsa concerned with
40:05 following injury and damage to the They are also involved in cytokine
40:14 So pro inflammatory cytokines that you hear , or cytokine storms that you hear
40:20 is they're related to covid in the hands it's inflammatory molecules, pro inflammatory
40:26 . Michael glial cells are responsible and in part control the release of these
40:34 inflammatory side economy. So they each their own individual functions. The piece
40:40 the three major subtypes. Astra cida , the legal tender aside from Michael
40:46 cells, the glial cells that were on the MS course, as I
40:55 to you, there's major subtypes of such as excited during inhibitory but that
41:02 mean that there are only two subtypes neurons in the brain. In
41:06 there is over 150 different subtypes of in the brain. Even more interesting
41:13 most of that diversity in neuronal subtypes from predominantly overwhelmingly dominated by diversity in
41:26 inhibitory gaba releasing neurons that are often to as inter neurons. So in
41:36 for us to distinguish between these 250 subtypes of cells, we can look
41:43 the morphology of the south and we also look at the connectivity of the
41:50 . Some of the cells that are cells that means those cells will project
41:58 axons long distances and connect to other and the adjacent networks or in the
42:05 lobes in the brain and some of external communication between neurons happens locally and
42:14 referred to as inter neurons and some projection cells in the brain are excitatory
42:22 dramaturgical cells typically pyramidal cells that you learn about and into neurons in the
42:31 that would control local activity but do really project long distances between different parts
42:38 the brain are into neurons that are that release gaba so have connectivity,
42:48 versus short range, excitability, excitatory and inhibitory gavel. In addition you
42:58 distinguish different cell subtypes based on self markers, neurotransmitters and neuro peptides that
43:06 either synthesize or release or receptors that may contain for specific molecules. Finally
43:18 the right here is the first publishing cellular action potential that was recorded by
43:25 and Huxley And squid giant axon in . So from technological perspective in in
43:37 of World War Two and during World two there's a lot of uh advanced
43:43 that are being developed by militaries including . S. Military. And at
43:50 point there are oscilloscopes that are fast . This this change in voltage.
43:57 very fast deflection from about minus 60 volts to about plus 40 million
44:03 200 mil of all change in a neuron. And in this case in
44:08 nerve and single axon. This is over the period of 2 to 3
44:17 in duration. This peak. So needed to have very fast equipment,
44:24 have to have their fastest oscilloscopes in to even visualize this. So it
44:29 enough that you had the ability to an electoral into the brain. And
44:35 was the easiest studies. It was stimulate the brain? You sink an
44:40 . You pass the current. You left motor cortex. On the right
44:45 moves we stimulate an emotional area and person starts crying or subject. So
44:54 were the easy to stimulate and observe behavior. Now the challenge becomes,
45:00 do you record what the neurons are ? So you need these fastest sillas
45:05 and us Navy military developed some of techniques and so there are these fastest
45:12 and enter into the labs also to biology. And to this day the
45:18 between silla scopes modern day computer controlled silla scopes even and some of the
45:26 pieces of equipment such as amplifiers and amplifiers are through B. N.
45:32 . Cables. It's a type of that is still used in the submarines
45:38 . BNC cables. So this allows Huskins and Hawksley to use the fastest
45:44 to record the the first actual potentials to take a polaroid picture of the
45:52 of the oscilloscope showing this very fast , calling it action potentials and then
45:58 that there's certain patterns that what we signatures or firing signatures of action for
46:06 . Most neurons have four domains. They have the info domain where the
46:13 is coming in from another neuron sensory , from the skin muscle, from
46:18 neuron into neuron projection into neuron the neuroendocrine cell integrated region which is the
46:26 conduct? I'll region which is the and then output region where secretion takes
46:32 . Or are you communicating to other ? Are you releasing modern neurons?
46:37 Acetylcholine neurotransmitter onto the muscle cells Or maybe influencing the contract ill Itty of
46:44 micro capillaries in the brain through this region. So input is mostly dendrites
46:52 soma. Um But there are exceptions that there's inputs that come into actions
46:59 well. Uh Then the integration is Selma's and the output is through the
47:08 ated axons. In some instances there unknown myelin ated accents as well present
47:13 the CNN. So if you stain neurons you can start classifying them based
47:22 morphology or their anatomy. And you a characteristic unit polar cells that you
47:29 find in invertebrates and they called the polar a single pole. So axon
47:36 dendrite are both looking up north bipolar , that's right is going north and
47:43 was going south pseudo unit polar. has two axons peripheral going through the
47:49 and the central going to the spinal and the cell body pseudo Unipol itself
47:55 be the sensitive also root ganglion south information to the spinal cord. Now
48:03 types of multipolar sauce that are shown which really indicates that most of the
48:07 in the cns are multipolar motor neurons the spinal cord motor neurons in the
48:14 cord releases several polling and motor nerves the spinal cord will release a single
48:20 on to the muscle cells to cause contraction. You have a multipolar cell
48:28 abundant in the cortex and sub cortical . As well called the parameter
48:36 In this case it's a parameter will of the hippocampus. It's an important
48:40 in the brain for memory formations and for emotional um information processing. And
48:50 this is a parameter will sell and you have a perkin ji cell of
48:56 cerebellum. For Kinji cells in the can have upwards 250,000 synapses formed in
49:04 single cell has one of the most branching in the verdict to branching which
49:10 observe anywhere in the cns As opposed the spinal motor neuron that for example
49:16 only receive up to 10,000 synapses. so this is helping us a
49:25 We already can visualize three types of multipolar selves but we need to know
49:32 about them. Of course we can that more psychologically. They're different.
49:36 are they different functionally in other words they produce different patterns or exact same
49:42 of action potentials? When do they ? How do they fire? What
49:49 ? And also with specific cell markers they have the same sets of uh
49:57 proteins that they express? And obviously and that's what distinguishes different cell subtypes
50:03 the slightly different expression of the genetic the same code that all of these
50:10 have but slightly differently expressed and to about the diversity and neuronal subtypes always
50:20 the circuit in this diagram which I very much from hippocampus. This is
50:28 hippocampal C'E. One area see a to corner simone or demons horns and
50:38 of a band area and that that resembles warren's ram's horns. You may
50:47 has three major layers, struggle for mandala shown here and wide start already
50:53 him on top but starting orients at bottom. So hippocampus a lot of
51:00 is referred to as R. K . Okay, archaic cortex, meaning
51:10 it is ancient that it's archaic and a three layer dominant structures. And
51:21 am I saying this to you? neocortex cerebral hemisphere is a new york
51:29 is a new cortex. The neocortex six layers. So that's why I
51:41 why hippocampus is called arcade vortex. that's why I like to say that
51:51 , he's trying to evolve into a cortex. So there's something very interesting
51:59 on in the hippocampus. There's also other very interesting parts of the brain
52:04 something very interesting is going on. as the confluence of the centers of
52:09 census in the angular gyrus that if of you have taken my understand sports
52:15 watched the wonderful ted talk by dr about that. So this this this
52:23 one of the most interesting parts of brain for me. Also the functions
52:27 the hippocampus performs. So now you're with its archaic cortex. It's a
52:33 layer uh cortex. It's located underneath cortex. It's it's not part of
52:41 neocortex. It's sub cortical, It's involved in memory formations and in
52:51 it's involved in semantic memory formation, that the hippocampus and the cells that
53:00 seeing in the hippocampal circuit here. when we get to the cells and
53:04 specificity of these cells, the cells the hippocampus circuit encode your stories.
53:12 of your story, semantic memory is the names, the places, the
53:19 that happened the years, the How many fish you got flat
53:29 what happened after in the story, proposing, somebody else solve semantic
53:37 Uh it's involved in encoding of this of the circuit but also involved in
53:45 recall of memories. So then your question should be okay. People campus
53:52 the south are showing grass is so and encoding and we call where is
53:58 storage? Very good memory storage is distributed throughout the cortex. But in
54:07 for you to drag out different memories will be widely distributed throughout the
54:12 And we'll talk about this again when talk about synaptic plasticity in greater
54:17 you need to drag out these memories vortex. You also have to engage
54:22 the Campbells. So encoding or formation memories goes through this hippocampal circuit in
54:29 diverse subset of cells that are involved mediating activity in the hippocampal circuit but
54:35 is the recall of them. And we also have finite space for creating
54:43 for recalling memories. And a lot times older memories gets raised by newer
54:49 or things that are more repetitious, associative learning or environment get ingrained more
54:59 through the plasticity processes that we'll be later. Okay well so this is
55:07 important part of the brain obviously. what's also important to know is that
55:13 part of the brain contains at least different subtypes of inhibitory inter neurons.
55:21 there was a local cells inhibitory they Gaba into neurons. They're local and
55:32 contains parameter self it's pretty boring Just one type of parameter cells distinguishing
55:40 between these three green and turquoise Karam, it'll south that are shown
55:47 is this molecule C. B. stands for called dependent. It's a
55:53 binding molecules. And some of the cells or cal didn't been positive.
55:58 means there's A C. B. and some of the prominent all cells
56:03 . C. B. Negative in stratum Koronadal is named stratum Koronadal because
56:12 of the, so most most of of parameter all cells will be fine
56:21 in this letter. But you can that some of the prominent cells especially
56:25 C. B. Negative cells will fine outside from the dollar layer.
56:38 . Ah so you have 21 subtype inhibitory cells in the circuit. And
56:43 have these parameters. Now inhibitory cells distinguished based on their morphology and when
56:51 look at the morphology the most obvious is if you have three layers ready
56:56 criminality and audience you stain neurons and say ok there's so much of these
57:03 cells that are located in the white which is the parameter alan layer 12456
57:11 . You don't need to remember And then there are so most of
57:15 cells such as 7 15 16 17 are so mostly located in the orient
57:23 and others are located in the ready of wire. So this is when
57:26 are exploring experimentally a tissue and you neurons and now you see these different
57:33 that are scattered everywhere. Now what distinguishes this inhibitor into neurons from one
57:40 . If you have 12456 living in same layer and they seemingly have similar
57:45 . So these thick clients and rab orange or in this case kind of
57:53 what is this? I guess fuchsia then would these thick lines or dem
58:01 And if you look 1245 and I have done writes that M.
58:06 AIDS from parana adala upwards a pickle rights to ready adam and base all
58:13 rights to orient 1 2 and four pretty much the same except that one
58:20 maybe 1/4 of the dendrites in in this other layer called strategy Latinos and
58:26 above already otherwise. So that is very helpful. And you will say
58:32 have 12345 subtypes of cells maybe even or 7 19 and 21 that's living
58:40 a dollar layer. And they have similar looking them drive. So you'll
58:47 seven cells. It's actually the same themselves. But then you say wait
58:51 second. Where are their axles? if their local inter neurons these local
58:57 neurons will be communicating information to each locally within the CA1 area of the
59:04 which is just one area of the . They'll be communicating locally here with
59:12 other and with the parameters uh So are their axons and where their synapses
59:22 . And so these purple thin lines yellow cops indicate where these 21 subtypes
59:29 inhibitory cells will contain there synapses. now you very clearly can tell that
59:36 number one although it looks very similar number two. Number four has their
59:42 that target basil. Then rights and target orients layer of the hippocampus.
59:49 then you look at these other cells as 21 that looks also similar to
59:54 morphological e it's also in the So now you can see where the
60:02 projections for the synapses from the syndicate very cells are located. And that
60:07 you that a lot of the inhibitory will place their synapses around the soma
60:14 the paris somatic regions of the excitatory all cells these excitatory parameter cells or
60:21 cells meaning that the information that gets in the C. A. One
60:27 of the hippocampus will be communicated outside C. One region only by the
60:33 around yourself. And so these different of inter neurons will flank them uh
60:42 architecturally in three different players and then . They're mostly somatic and para somatic
60:50 . But then you will see that are certain cells like seven. Number
60:56 of my favorite cells. That's Orients a Nossa molecule are abbreviated as an
61:05 . A lam style. It's really because it's so almost sits in the
61:11 orients often in the base of the . Orients layer as these massive lateral
61:20 drives projecting here horizontally and then this this very long axonal axonal terminals that
61:29 the ethical and distal parts of the all cells. And this looks awesome
61:35 the lower layer. So it expands all the three major layers of the
61:41 and terminates in the and then you'll well why do you keep saying it's
61:49 layers if you now added the fourth because technically it's still referred to as
61:55 three layered structure. But as I you it is trying to evolve into
62:00 six layer structure that's a lot more than just three layers. Shut
62:08 And uh Orients Lughnasa Maloku Larry is cell that has this axon spanning across
62:14 three layers and just targeting the optical of parameter cells. So as you
62:22 at this diagram you know treated as complex informational diagram. Any functional complex
62:30 will say like that's very interesting because 21 different subtypes of cells. They
62:36 differently. They have different done They target different parts of these parameter
62:41 and they will locally influence whether these cells and what message these parameter cells
62:48 going to then convey through their projections the adjacent regions of hippocampus or outside
62:56 the hippocampus. Uh But still you anatomy and the drink and exotic
63:04 Number two and number four look exactly same. So if you just did
63:09 anatomy you would still say that two for the same some type of
63:14 But if you did staining for specific markers as I said only a subset
63:21 genes get expressed by these cells making individual subtypes. Different individual subtypes of
63:29 . So number two, South will P. D. Which stands for
63:33 Volumen. It's also a calcium binding . The number of four cells they
63:40 have privilege in them. But instead have other markers that are referred to
63:45 C. C. K. Who the system Kinen inv igloo three which
63:50 particular glutamate three state. So now using this collection of all of these
63:58 knowing the morphology of the self, their location, knowing the cellular markers
64:04 knowing the patterns by which they produce potentials. We can definitively distinguish between
64:11 subtypes bob sells in these local circuits so you can see that there's 21
64:20 of inhibitory cells and pretty much just where the cold, Indian positive or
64:24 subtype of the projection excitatory cells that control that will convey that information to
64:30 adjacent regions of the brain. An understanding that these inhibitor into neurons
64:36 local control of local circuit activity is very important. And given the complexity
64:44 the diversity of these cells, you the ability to have multiple computational modes
64:55 various levels of complexity because of the of the cells and the way they
65:02 . And so this is the last that I will show you today because
65:08 coming up almost to the end of time. But today is diversity of
65:15 behaviors of neuro cortical neurons. If were to blacken the lecturer in the
65:19 and record activity from these neurons and will present the exact same stimulus through
65:25 micro electrode into these cells. These will produce a different frequency and a
65:31 pattern of action potential. And this final distinguishing factor between these inhibitor
65:37 So if you were to sink an and cell number four versus cell number
65:44 , these two cells will produce a pattern of action potentials. And I
65:50 illustrate that locally. So this is delayed stuttering stimulus, started on stimulus
65:56 then you start producing these these lines you're seeing here are action potentials.
66:02 it starts producing inconsistent non continuous le of action potentials. This is a
66:19 neuron, there's other neurons that you current into them and they at low
66:25 of low stimulus produced low frequencies and stimulation levels produce higher frequency of action
66:38 . And so each one of these is essentially producing its own dialect or
66:45 own speech. And this is how can distinguish between these different subtypes of
66:51 . You have to record activity. have to determine what kind of pattern
66:56 action potential the cell on the left the cell on the right producers.
67:00 you give them the exact same you can recreate the morphology of these
67:06 using a stain that is inside the . And that stain called biocyte manure
67:14 will leak inside the south and will post hawk. After the experiment the
67:21 morphology of these cells. So you the exact location of the sauce,
67:26 dendritic trees in black that's internal This is an alarm cellar was showing
67:32 earlier. This is a pyramidal cell the straddle pyramidal in layer here has
67:37 extensive dendritic tropical tree basil gun rights an axle on coming out into this
67:43 plane outside and finally cross staining the that you're recording post hawk experimentally with
67:52 markers such as providing them such as statin or neurobiology and the the dye
67:58 you injected yourself that you want to And so definitively doing all of
68:05 The morphology revealing the morphology revealing the that the acquiring properties of these
68:14 Then the membrane properties of these the connectivity where the synopsis are located
68:21 the cell markers will allow you to in this case between putting one different
68:27 of cells in hippocampus but overall in brain you would have to apply a
68:33 of all of these techniques to identify plus different subtypes of cells that I
68:40 mentioned. So this concludes our second and we will carry on with information
68:49 membranes and we will carry on information action potentials, neurotransmitter release. And
68:56 looking very closely about dramaturgical neuro The rules and the major receptors that
69:04 involved and the pharmacology of these Different binding domains of these protein
69:11 In building our understanding of not only diversity of cell subtypes as we did
69:17 in different circuits of the brain but understanding how glued innate signaling happens in
69:25 brain. So we will start with and actually spend more time with
69:30 Although I think it's more interesting to about inhibition. The diversity of
69:37 But in reality when you look at electro physiological studies and the C.
69:42 . S. Still overwhelming majority of are performed from the parameter. Will
69:48 most of the experiments and recordings. easy to identify. It's a thick
69:54 . It's easy to block an electrode it? And if you record preventing
69:58 well it's more difficult. It's more experimentally. They're harder to patch ah
70:05 harder to place an electrode engine. also if you reported from number seven
70:12 you have to prove the reviewers you from number seven And not from number
70:19 and that takes more time. It more effort. So it's easier and
70:23 a lot more acceptable in the experimental to say the phenomenal cell recordings and
70:29 reconstructed morphological and maybe once or maybe didn't just took a picture of
70:34 Everybody knows that everybody is happy with and you are. It's easier to
70:40 do this kind of work. So of the electro physiological studies you'll still
70:45 is done in a projection parameter Although I think most of the interesting
70:51 things that enable these parameter sausage compute the and communicate that information to the
70:58 circus is happening within the diverse subset the inhibitor integral. This concludes our
71:05
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