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BIOL 4315 & 6315 Neuroscience Mon-Wed 1-2.30 PM - Neuroscience Lecture 03 Neurons 1
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00:02 This is the third lecture of And we're now starting to talk about
00:08 and glia. And in particular, we are talking about those two major
00:15 of cells in the brain, the are a lot more abundant. So
00:19 account for about 90% of all of total cell mass in the brain and
00:24 are about 10%. So I say neurons, I like chips in the
00:28 chip cookie Gle which stands for glue like the dough and the cookie is
00:37 interesting without chocolate chips in it without , but there's no cookie without a
00:44 . So without glia, there is brain and there is no neurons because
00:48 plays an intricate part in the development the brain and homeostasis of the
00:54 interacting with neurons and the communication and uh connections that they form and how
01:01 communicate with each other. Once the game in the brain is mainly
01:05 the stain because only with the help these stains, which was missile
01:10 And remember the differences between this stain that it gets absorbed by all of
01:14 cells and the Golgi stain. Gets only by a fraction of neurons.
01:20 , in case of Golgi stain, exposes all of their processes in great
01:25 , the soma, the dendrites, axons and so on. No,
01:36 we had a good view of these , if you recall, there were
01:41 predominant theories, the reticular formation versus neuron doctrine. The proponents of reticular
01:50 including uh Camello Golgi argued that the is a continuous sensum that's surrounded by
01:59 same ox cytoplasm and a single membrane the whole brain. And Ramon
02:06 as I said, was very forward and he described how neurons receive information
02:14 then drives. He put these arrows suggesting that as they receive this
02:19 that information is traveling into the selma it probably gets processed and as it
02:29 processed, it gets sensed by these where that are going along the darker
02:36 . These are the axons. So proposed that these connections that are formed
02:42 axons onto dendrites that they are potentially permanent, that they may be plastic
02:49 . And as such, they can a new, you can lose some
02:54 these connections. And he introduced unbeknownst him, this concept of synaptic plasticity
03:01 neuronal plasticity where the connections can become or weaker, you can form greater
03:07 of connections between active networks or you the connections and reduce the number of
03:14 between networks that are not that OK. And uh so with this
03:23 development and this thinking and this kind a flow of information, he also
03:31 this principle of dynamic polarization where he that inputs coming in into dendrites,
03:36 to SOMA and traveling through axons. that's sort of a one directionality for
03:41 polarity of the traveling of the Uh Now, if you look at
03:49 prototypical neuron, which hopefully you can no, you can't trust them.
04:05 not switching. Is it no? ? So, in most part,
04:14 we were able to understand the inner of neurons, we understood that these
04:21 are like other cells that we, we know and other organelles that you
04:26 started in those cells. It has nucleus has mitochondria as golgi as
04:33 It has smooth endoplasmic reticulum. We rub on the plastic reticulum covered with
04:40 the ribosomes and ribosomes. And then have these specialized formations that are somewhat
04:46 from other cells in the bodies. have these extensive dendritic trees and dendritic
04:51 that we call dendritic spines on And we also have these dendritic trees
04:58 dendrites that we refer to as apical basal. And we call them optical
05:05 . Because in many cases when we neurons, we study the type of
05:11 that is called the petal cell. the petal cell has a pyramid like
05:17 . So at the top of that , you have the apex and therefore
05:22 dendrites that are located at the apex the optical number. This is the
05:29 . OK. This is the apex these are referred to as optical
05:35 And this is the base right here this pyramid. And these are referred
05:41 as basal dendrites. And in addition the dendrites, it has a specialized
05:48 as it you can see, the has these myelin segments has myelin that's
05:56 around the axon that provides for the of the Saxon, almost like an
06:02 insulation of the wire that will allow the Saxon to generate the action potential
06:09 this axon hillock. And that action will get propagated down the axon that
06:15 preserve its amplitude all the way until reaches the axonal terminal where there's going
06:23 be, this is where action potential regenerates, it reaches the axonal terminal
06:30 it causes the release of the neurotransmitter the synaptic cleft from these vesicles that
06:38 neurotransmitters. Ok. So a lot times we refer to this as presynaptic
06:45 is the side that is releasing your from the vessel, right? And
06:52 you recall postsynaptic densities, that's postsynaptic . So these would be located
06:59 for example, located on the dendrites will contain receptors that we also refer
07:08 postsynaptic density. Ok. So this PSD because this cell here this done
07:14 here. It's post synaptic versus So, so the cell that is
07:25 is called postsynaptic. The cell that releasing its presynaptic neuron. We have
07:34 same things that happen in all the . We have gene transcription, uh
07:39 rnarn A to get transported, exported nucleus to probably some sort of a
07:46 mechanism. Then from RN A, have slicing into a messenger RN A
07:54 then that messenger RN A gets translated a protein. So very basic things
08:02 you already learned about basic genetics, splicing of the RN A into messenger
08:08 A is an interesting uh process. there are some mistakes that are made
08:14 variance that are made are called splice . A lot of us are splice
08:21 of each other to a very small . However, if there is too
08:27 of the variance during a sli it can also potentially lead to dysfunction
08:35 a sort of a neurological disorder. we live in the post genomic
08:42 So we understand the genes really And we can use several interesting techniques
08:49 we're discussing here. For example, techniques to understand the brains as
08:55 And this is again rudimentary at the of uh synthetic DNA. But there's
09:02 you may hear these days RN A which is sequences of RN A and
09:09 comics and understanding the level at the level of the transcription these things.
09:15 what is illustrated here some useful techniques for example, you have a question
09:21 you have two brains, brain, and brain two. And it turns
09:25 that brain two is a phyla And you would like to know what
09:30 different about the genes in the epileptic too versus normal or non epileptic brain
09:39 . And for that, you could gene micro arrays and these micro arrays
09:46 shown here. They're essentially microscopic slides microscopic blades that will contain thousands of
09:55 little wells. This is simple violence showing tons of these wells that will
10:00 thousands of 10,000, 30,000, 50,000 in them. Each one of these
10:07 will have a synthetic DNA with gene sequence because we understand what sequences
10:17 are what genes essentially we can now the replica of that. It's
10:22 So if you have 10,000 of these , each one of these wells can
10:27 a unique synthetic DNA sequence representing a so far so good. And so
10:36 sort of had a sticky velcro here a certain sequence. Velcro is just
10:41 analogy of something that needs a counterpart stick to, right. So now
10:48 take these two brains V from brain , it's labeled red V from grade
10:55 labeled green. And you put this through a certain procedure. So you
11:03 the neurons you treated chemically and then apply this mixture here from testing onto
11:12 microplate on to your G micro little or hopefully you have automated because if
11:19 have 5000, gonna take you a time to do a little bit of
11:23 works 5000 times and start making a . A lot of these things are
11:28 automated, upload 100 at a five PT and so on.
11:34 what is shown here is that you tag these synthetic DNA pieces with a
11:40 mark of a fluorescent one or color either way the fluorescent fluorescence is in
11:50 . So if the gene has an expression of both races, that means
11:56 the expression of those particular genes have changed, it's gonna appear yellow.
12:02 this case, it's almost a little like color, mixing red and
12:06 people are also red and green. you young genes reduced expression in brain
12:15 will blow red. So now you applied, you have the pieces of
12:20 , you applied your brain Homola. . Now you're gonna see in this
12:28 , what are the complementary has to complimentary sequences that will bind to this
12:37 . It's like really sophisticated talk. the sequences are not complimentary, it
12:43 float up. So now you have equivalent expression, you can see which
12:50 are used expression. You can see genes are used expression in brain one
12:56 brain two. It's a pretty good . You can also see which genes
13:00 increased expression, not just reduced It's a pretty good tool to give
13:06 sort of a, a bird's eye . Of what may have changed in
13:11 end if you have 10,000 of these wells and you're studying 10,000 different
13:17 uh, difference between normal and epileptic could show you difference in 500 different
13:24 . How do you know which one important? And say, oh,
13:27 gonna see which ones are the most regulated? The 10 most stuff regulated
13:31 the mo the 10 most down regulated already are sorting through based on some
13:39 analysis of what genes are over expressed under expressed. And let's say epileptic
13:45 , you're gonna probably cross examine yourself existing literature. You're gonna check you
13:51 your mentor. The mentor is gonna at the list and say,
13:55 you got these up regulated on these . Well, we're really interested in
13:59 two in my lab. So go the rest of your five year dissertation
14:02 these two genes, see what And then you can be like Ramonica
14:06 and say, I wanna do it two others because I think they're really
14:09 . It's like, don't ask to it and ask for forgiveness later as
14:14 as you're still working on the things are most important for you.
14:18 Uh And then within the regulatory and boundaries of whatever you do.
14:25 all right. Well, uh, is ok. But what about the
14:28 500 what about the 200 that maybe regulated down regulated? Let the other
14:33 docs grab the other two, the graduate student, the other two and
14:37 , slowly, slowly, slowly, start making sense of what's happening in
14:41 brains. Does it give you a of what part of the brain was
14:47 ? If you take whole brain and homogenize it and to no, it
14:53 . Well, we give you more . Let's say you dissect it out
14:57 piece of the brain such as And you compared hippocampus from epileptic brain
15:04 hippocampus. And now you probably out this 500 genes that change, maybe
15:08 have a smaller pool of over expressed under expressed genes. It still is
15:14 really good kind of a bird's eye of the changes that happen uh in
15:19 tissue and in the brains, normal epileptic neurologically, uh uh brains with
15:27 disorders, brains that have been genetically engineered. And in this case,
15:34 experimental neuroscience quite common techniques is to out a gene, it's called knockout
15:43 . Because ultimately, apart from just what happens to these genes, whether
15:48 upregulated or down regulated. You wanna what happens if I take this gene
15:53 of the animal's brain and you wanna as specific again as possible. What
15:59 if I take the gene out of animal's hippocampi, a specific cell subtype
16:04 the hippocampus, you're getting a lot specific in what you're doing, but
16:11 gene has been deleted or knocked out in mice where you have native gene
16:16 is being replaced with a modified So you have splice variant,
16:22 And I said that if you have of that variance, sometimes that can
16:26 a dysfunction in the protein that gets , that protein could be a channel
16:32 and it will have a mutation on and that mutation could be causing neurological
16:39 . That mutation of, let's say protein like voltage gated sodium channels.
16:43 about you, which you will learn lot in the next few lectures.
16:47 what you wanna see, what if just don't eliminate that gene? But
16:51 if I replicate this mutation that we in epileptic brains? But if I
16:58 that mutation in the gene in the mouse, why would you want to
17:03 that? It's all about models, ? And when you're gathering data,
17:08 have to repeat the results. So you're gonna go out in the wild
17:12 search for epileptic mice, good So you have to have a
17:16 you have to have a uh uh controls of normal brains. If you're
17:22 genetic manipulation of your working with trans trans genes, knockin or knockout
17:29 you have to have a certain population of that population size of the sample
17:37 you test, that you compare to else that shows under a confidence
17:42 a statistical difference, right? Let's to do the science and the science
17:48 , right? So you're comparing the . So you want to know,
17:51 of knocking out a gene, you to replicate it, you're gonna knock
17:55 a faulty gene, it's going to be there, but it is going
17:59 be uh uh a replica of what in nature when mice or even people
18:07 epilepsy because we share a lot of , a lot of sequences and a
18:10 of proteins with other species, trans , genes are introduced and over
18:16 So you can al also over express gene. What happens if there's too
18:20 of this gene. Therefore, hopefully much of this protein down the line
18:25 something else. Almost for neurological many of which have genetic biases or
18:33 a basis. Sorry. Um We a lot of neurological disorders that have
18:40 basis that have genetic background. We'll about epilepsy and we'll talk about the
18:45 disorder that affects a specific gene that seizures of very severe forms of
18:52 And so we want to understand, want to understand with these mutations in
18:56 . That's why we use these models animals. This is not in
19:01 this is in mice. Uh And want to understand because we cannot help
19:06 humans, let's say they have a condition, untreatable form of epilepsy and
19:13 a child and the child is So we have to understand what's wrong
19:19 with that child or what's wrong with patient. We have to look for
19:23 in the blood. We have to for markers in the in the
19:27 Once we identify them, we need understand them. So we go into
19:32 models to understand these things, we the genes. We understand the
19:36 We understand where they're expressed, where can be found ultimately to go back
19:42 help those patients that are having untreatable or other neurological disorders. Uh protein
19:51 can be really slow floating ribosomes that uh interacting and translating recreated proteins and
20:03 proteins that could be attached to the or membrane attached proteins. And you
20:10 this uh rough on the particular the that number and associated a lot of
20:16 we study in this course is going be membrane associated protein. So we're
20:21 talk about uh uh ion channels. gonna talk about G protein coupled receptors
20:28 they're all either transmembrane or membrane associated that we'll study protein destiny isn't determined
20:37 the Golgi apparatus. Does this guy familiar? It's the same go.
20:44 he also is responsible for discovery of good, good, good, good
20:50 him. Mitochondria, which is the source of energy produces a TP.
20:56 it takes the dietary stored energy protein sugar fat as pyro acid
21:03 pyro acid goes through the oxidation cycle a TPO gas of CO2. Then
21:10 TP is a denison triphosphate. It's major major energy molecule in the
21:19 but also in the brain. And very important for the brain because your
21:25 mass of the brain is about £3.5 so. In weight, you can
21:31 your own math based on your body . The brain is not going to
21:37 by much the mass of the brain the body weight will fluctuate by a
21:43 . Some of us are petite, are XX XL sizes, right?
21:48 can do a calculation of what uh fraction of your weight is your
21:55 £3.5. So if an individual is then £3.5 is 1.75% of the total
22:07 mass is the brain, right? it will consume about 20% of the
22:16 body. So it demands a very energy uh supply and there's a lot
22:25 energy turnover. So it's a small that basically uses 1/5 of all of
22:32 energy. Does it, it, consumes a lot. It needs to
22:37 these energy sources, it needs to them stable and reliable. In order
22:42 function. Normally, plasma membranes are bilayer. These phospholipid bilayer are comprised
22:53 the liquids and phosphate groups. Hydrophilic phosphate groups that have fatty acid
23:02 The fatty acid tails are hydrophobic and took inside to meet each other and
23:09 has a hydrophilic. So they're facing the fluid, uh aqueous fluid of
23:15 cytoplasm or aous fluid of the extracellular , interstitial space, interstitial fluids.
23:24 within the membrane, we have we have cholesterol embedded in the
23:32 Some of these proteins are transmembrane That means that they actually contain an
23:39 channel within the protein that will allow the passage of ions and small in
23:44 of a small molecules. Other proteins now channels, they are associated with
23:52 coup. So this is G uh protein co receptors, which is still
23:58 receptor will receive information, but it conduct anything. It doesn't allow the
24:04 of molecules through it. Instead, is linked to this G PRO complex
24:10 is going to activate downstream intercellular cascades the secondary messengers. Typically, we
24:19 have uh glycoprotein carbohydrates. Uh So lot of times neurons and cells in
24:28 are referred to as sugar coated. are important for cell to cell recognition
24:34 other features. This whole membrane is fluidous, it moves in space.
24:42 you click on this link, you watch a very short video of about
24:47 minutes. Uh because of some technical , I'm not gonna play that
24:52 you can do it on your And you will also see that this
24:55 kind of a common theme in my materials that I cross link in certain
25:03 . I will also cross link sometimes open access PDF S or articles.
25:10 And you can use that also as tool as a helping tool to remind
25:16 what we're talking about. But plasma follows what we call a fluid mosaic
25:23 . It's fluid because the structure and of the phospholipid bilayer changes, it's
25:32 as it's mo moves, it's a because it's comprised of all of these
25:38 elements. The carbohydrates, cholesterols, membrane associated cytoplasm to cellular space associated
25:46 . So it's a mosaic. And can it be that this plasma membrane
25:54 its shape underneath the plasma membrane and its structure. You have cyto skeletal
26:01 . These cyto skeletal elements is sort like the structure and the frame of
26:07 house. They're holding up the overall of the house. In this
26:12 the overall shape of the cell. these elements, cyto skeletal elements,
26:18 are three types of these cyto skeletal . We have microtubules which are the
26:23 . We have neuro filaments, medium and we have microfilament require the active
26:30 here that are the smaller cytoskeleton And these elements, what they can
26:38 is they can polymerize and form longer and they can break up or depolymerize
26:45 shorter chains of acting for micro filaments tubulin for microtubules. And you can
26:54 of it that shorter chains would be rigid, can't really move short,
26:59 longer chains would be more elastic and move easily. And so there are
27:07 that happen underneath the plasma membrane, adjustments as they happen underneath and the
27:14 skeletal elements can also cause a changes the shape of the plasma number that
27:21 supporting above. It's the same as change. The did a little remodeling
27:25 your house and you added another So OK, so you can do
27:38 by rearranging the cyto skeletal elements. then what happens to your house?
27:42 structure of the house is different. have an extra bedroom. So the
27:46 of this membrane is different, you an extra bedroom. The other feature
27:52 uh contributes to the fluidity in the membrane is the fact that these molecules
27:58 are embedded, especially proteins can move the plasma membrane. So they will
28:05 will float within the plasma membrane and will float around very fast speeds and
28:11 they can flow through entire cells in matter of milliseconds. It's very fast
28:17 of these uh membrane associated and even proteins that we're observing in neurons.
28:27 is illustrated here is again, this scaffolding of neuronal membrane that's supported by
28:35 cyto skeletal elements. And in we have here cross section through an
28:44 . So an axon was cut, is a axon and if you remember
28:50 Exxon that comes out to another one , excellent that goal it has myelin
28:57 it. OK. And what has done is that this axon now has
29:03 cut in half here and you expose wrapped around it on both sides.
29:12 also you expose certain internal uh morphology of this axon. And as you
29:22 a cross section through an axon in outside, again, these are the
29:25 sheets enveloping around the axon for protection insulation and inside the axon, you
29:33 these microtubules. So they appear sort a spaghetti, you know, all
29:40 , these are also micro tullar highways they're very important for Axonal transport.
29:48 that get synthesized, produced near the . They need to be transported into
29:53 terminals, suon terminals such as synaptic or neuropeptide vesicles. And so you
30:01 have certain molecules that are engines or for transporting, for example,
30:10 This is an example of Ken molecule will transport the vesicles from the SOMA
30:17 the periphery. And then there's also to be another molecule, it's called
30:22 . And that molecule that transport engine gonna be transporting things from the periphery
30:28 into the SOMA. But there will riding along this micro tubular highway.
30:35 it's very important that you have a structure riding along this micro highway,
30:42 a certain structure of integrity and stoop and these highways. Because what happens
30:49 Houston, if there's traffic jam and accident on two highways out of
30:57 everybody falls behind about half an hour eventually it kind of all affects
31:03 Even if you're not in the it could be two miles away,
31:06 the traffic has slowed down significantly because that accident, that could be miles
31:11 of you. So the same happens . If you have something that is
31:16 about the structure of the magnitude of loss of matins or entanglements of these
31:26 , what happened if we took like and wrapped it around 610 I 10
31:32 be a big mess, right? that's, that's what can happen
31:35 So you have to have precise uh here in order to have really good
31:43 . This image illustrates the staining in for the smallest active empowerment here.
31:53 you can see that the smallest Akron elements are located in the very
31:59 boundaries of the cell and the very supporting the outermost vel brain structure of
32:05 neurons in yellow, you have tubulus comprises microtubules. And you can see
32:14 most of the state or tubulin and is really the core integrity around the
32:24 , ok, almost like the the major foundation and structure around the selma
32:31 . But also you can see extending the processes as as the microtubule
32:37 Also this is a really nice illustration uh there is a pattern and there
32:45 a pattern and organization of the cytoskeleton . They all are intertwined, they
32:52 located sometimes in the same locations. there's also specificity for the acting to
32:59 the most in the most distal part the outermost boundaries of the plasma
33:07 Axonal anatomy is such that you have major axon that comes out and usually
33:13 axon will travel certain distances. But this axon projects to let's say external
33:24 , it can also send out So we call these ramifications for basically
33:32 bifurcations of the axons and uh several different collaterals that can have their own
33:43 . Uh Axon Hill op is where action potential is produced. Axon proper
33:48 the whole axon axon terminal is where have the release of the neurotransmitter.
33:55 . Uh There are some differences between and SOMA that they have unique protein
34:02 . There are certain proteins like voltage sodium channels and other voltage gated channels
34:08 g protein coupled receptors that you will in the axons. But you will
34:12 not find them in the sun or them to a very small degree.
34:16 other proteins you'll find in the dendrites you will not find them at all
34:21 not to the same degree in There's subcellular differences in the expression and
34:28 of these unique protein subsets in axons dendrites and Somas. Uh and the
34:35 er and the plasm reticulum does not to axon and this is a little
34:40 more about axonal anatomy in the sense this is the axonal terminal, external
34:48 , as you can see is also with mitochondria. So a lot of
34:52 energy goes into the synaptic transmission to causing of the vesicle, fusion of
34:58 of the neurotransmitter and recycling and rebuilding the internal content of that vesicle.
35:04 you need a lot of energy in synaptic terminals. You have a lot
35:08 A TP located there. You also these synaptic vesicles that are sitting in
35:15 we call active zones. So a of them will be floating around an
35:20 terminal, but quite a few of will be sitting what we call prime
35:25 next to the membrane. These vesicles soon as they depolarization, this action
35:31 will arrive in the external terminal. soon as there is depolarization, an
35:36 of calcium. Here, the basils use the plasma membrane neurotransmitters will get
35:43 into the synaptic flap. This is 20 nanometer space here will travel across
35:48 flap and bind to the receptors in posy dendrite where you have the posy
35:54 that we discussed. Yeah. So really have this electrical action potential that
36:01 the release of the chemical, the that chemical gets released and it binds
36:06 the posy tic receptors. It causes change in the membrane potential which again
36:11 an electrical response and inevitably po In addition to just change in the
36:17 potential, there will be a change the chemistry of of uh the postsynaptic
36:25 as well. And synaptic transmission, synaptic transmission, precise formation of the
36:33 spines, precise outputs that you see axons are important for normal brain
36:40 And if you have impairments in synaptic , and we will study certain diseases
36:45 affect uh certain chemicals in synaptic transmission leads to neurological disorders such as for
36:52 , dopamine dysfunction and synaptic transmission. dopamine is associated with motor disorders like
37:00 disease as opposed to serotonin, which another chemical and impaired neurotransmission of serotonin
37:09 associated and is known to be a of the mental disorders such as uh
37:16 depression, for example. So we're end here today. I apologize for
37:22 technical difficulties I had here today. Hopefully we'll overcome them for the rest
37:28 the time we be here. Uh a good rest of the week,
37:33 stay safe and dry over the weekend I'll see everyone here on
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