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BIOL 6397 Cellular Neuroscience (27770) - Wiring the brain 1
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00:02 This is the first lecture of Wiring brain in cellular Neuroscience. And I
00:09 this image because I always uh ask , I tell me what it's
00:16 what it thinks kind of. And I forgot there's a lot of control
00:21 . So when you think about wiring brain, there's one thing that we
00:28 thinking about wiring the brain in the century that was really trying to figure
00:32 how the brain is wired, how circuits are formed inside the brain.
00:37 we're still figuring it out. We have not figured that out, but
00:41 already started thinking about a different type wiring. And that is how we
00:47 wire into the brain. We talked deep brain stimulation for uh medical treatment
00:53 Parkinson's disease. Uh But neuralink, example, is not only they are
01:00 only targeting the quadriplegic and paralyzed potentially thinking about how it can be
01:06 , intertwined with thoughts with actions that individual may make through wires that are
01:13 in the. So it's kind of you can think of wiring the brain
01:16 to understand how we wire the We can also wire into the brain
01:22 better. Um So wiring the This is from one of the recent
01:31 , it's not so recent, I it's maybe uh 12 or 13 years
01:37 , but it is a pretty, complex uh structure. It is way
01:45 complex than other organs in our We have about 85 billions of
01:54 So we're talking about trillions of connections form between among those 85 billion
02:01 Uh If you recall in early the great starts out. First of
02:07 , it's just like a plate kind a thing, then that plague merges
02:14 over and becomes more like a kind a tube kind of a thing rolled
02:20 . And this process of neuralation, neural tube formation uh from the tube
02:27 then subsequently during the embryonic development. we're talking about humans, in
02:34 you have neurogenesis. So a lot things that happen in the developing brains
02:40 in fetuses. Um In your it was also discussed that in certain
02:47 , certain neurogenesis or wiring of the may happen later post natally. But
02:54 you, for example, want to understand what happens with the birth with
03:00 formation of the synopsis, with the formation with connections that are formed and
03:07 these pathways and modified. Then um understand that you really have to understand
03:15 early development, understand the the cells are involved, the molecules that are
03:20 . And you really have to look it in the early embryonic development.
03:26 in humans, it's like 14th week gestation through about fifth month of gestation
03:36 you have a lot of these processes new cells are being born. A
03:41 of cells are being born. We a lot of connections, those connections
03:45 refined, they establish correct pathways onto based on chemo attractants, chemo
03:55 So adhesion molecules guys like radio glial that we'll talk about. And in
04:02 end, it gets fine tuned by . And this all speaks to the
04:07 that they are both nature and nurture in this process that there is a
04:14 , I always say that the brain like a really complex self assembly based
04:19 the code, the genetic code that it gets in initiated and it's a
04:24 complex structure. And you'll understand maybe we're different a little bit in our
04:30 too if we look at the molecular during the development and how that guides
04:36 formation of neural circuits and the molecules guide the formation of neural circuits.
04:41 this fine tuning based on experience or dependent tuning, activity, dependent
04:48 In a way, it's something that happening constantly with, with,
04:51 with nurture, with the development the , the environment you're exposed to
04:57 stimulant environment you're exposed to also. let's use this example again of the
05:06 system which we understand pretty well, look at this and it's retinal genicular
05:14 because you have retinal cells in the in the eye and the photoreceptors that
05:21 responsive to light. And an intrinsically retinal ganglion cells that are responsive to
05:27 in the retina. The ganglion cells form the optic nerve which is cranial
05:33 too. And the portion of that , which is the temporal side,
05:39 temporal side of this retina is going stay on this side if so
05:46 So that means that the axions that out of here, they come to
05:50 opticas and they decide that they're gonna this direct and the nasal retina comes
05:57 the optic. And it says instead saying if the later it's gonna cross
06:01 pump the water. So from retina the lateral geniculate nucleus, and we're
06:07 look at this pathway again later So retina geniculate retina, lateral geniculate
06:14 and then genicular cortico because you have geniculate nucleus projections that primarily innervate layers
06:24 and from layers four to communicate to higher cortical layers. This is in
06:29 primary visual cortex which we call the cortex. And most of the inputs
06:35 different layers of the thalamus that is representing activity from individual cells. So
06:42 layers are monocular, the layers in will process information from only one eye
06:49 that information still remains monocular all the to layer four of the cortex.
06:55 then lowly in layers to three, information gets merged again into binocular type
07:01 information. So this is a visual pathway and we'll come back to
07:08 but that's a lot that needs to happen. Exxon need to find
07:15 way, they need to be They need to find the correct
07:19 It's not just the direction I'm gonna left versus right. Once you approach
07:26 is a six layer structure, I to go to layer one, I
07:31 to go to layer two. Then there, I have to go into
07:37 and then layer four. So there there is this whole complex development and
07:43 specific in this what you call now doubtfully developed visual system. This is
07:51 what kind of brain is this? is a rodent brain. So you
07:58 be able to recognize that by a large olfactory bulb. And also kind
08:04 a uh the shape that is a alligator and not much of a
08:08 like not a 90 degree bend like see in the upright um animals and
08:16 . So it's pretty complex. You all of this system that self assembles
08:23 and the axions that need to be . They recall that these projections from
08:31 temporal weapon that will innervate 23 and very specific players in LGM. And
08:37 the contralateral side, it will innovate 14 and six from the cortex.
08:50 mean from the LGM, the inputs going just a reminder to the
08:54 It's mostly innovating in layers four from four, sending the information layers 23
09:03 layers 23 have a lot of intracortical . And that's something really important because
09:10 think that maybe that's one of the of humans is this really uh elaborate
09:19 in between different cortical areas that happens layers 23. So there's a sensory
09:24 coming in from deep layers, gets within the local columns in the
09:30 But then these guys lays 23 will that communication throughout. And that's how
09:36 able to bind the sense of smell a sense of sound and the sense
09:44 visual information and so on and so . So in in in in layers
09:51 , in particular, we have a of petal cells. So these parameter
09:55 will have lateral connectivity to other cortical . And then the primary visual cortex
10:02 cortex is referred to stride cortex. we already alluded to stride cortex is
10:09 fact that in the primary visual uh ocular dominance columns and one of
10:16 darker zones represents ocular dominance from one . All the darker zones, all
10:22 wider zones represent ocular dominance columns from opposite side from the other eye.
10:28 if you stain um this layer in particular, peel off the superficial
10:36 . In particular layer 23 and Layer four, you will see that
10:41 four will have these what we refer as ocular dominance columns. So we'll
10:46 back and talk about ocular dominance columns elasticity in the following in the following
10:54 . So layers four, again, close to the input comes in layers
11:01 and layer six or four coming in six is where the output already goes
11:08 LGM. And this is a pretty circuit. But the main point of
11:13 is if you have inputs coming in this layers, for the inputs are
11:18 segregated, left eye versus right eye . In layer 23, the inputs
11:23 binocular and then 23 allows to spread information, visual information to other visual
11:30 , to auditory areas and so on so forth. And the deep layers
11:35 project back into the subcortical regions back the LGM. So apart from within
11:41 geniculate cortical, we also have cortical projections, but we don't have genicular
11:47 projections back into the retinal. And loops between the uh thalamus and the
11:55 are very important. These thalamocortical loops uh many different instances. And we'll
12:01 it in several instances in discourse later the course. OK. So first
12:06 all, this area actually is something uh is fairly new to me in
12:16 sense that I think it's really cool development of the brain, the birth
12:24 new neurons and how things happen. uh I'm just becoming increasingly more interested
12:33 this code of the pattern. How a code for the whole pattern.
12:40 it was long postulated that neurons genesis birth of these neurons doesn't happen everywhere
12:52 the brain that there are specific zones the brain. And those are referred
12:59 as ventricular zones and sub ventricular zone when neurons are born, we also
13:09 and we also saw earlier when we glial cells that radial glial cells serve
13:15 guides for neurons. But it also mentioned to you that radial glial cells
13:22 precursors. And in fact, most them are neuronal precursors. So apart
13:30 being the guides, there are also precursors and you have the cells that
13:39 from this ventricular zone closer to the . In this developing brain, the
13:46 surface is the surface of the the PM monitor and it migrates up
13:54 this marginal zone through a number of and goes back into this ventricular c
14:03 . And there it goes through a division where it becomes radial glial cells
14:10 stays rad glial cells or it goes asymmetrical cell division. And one of
14:18 which is a neuron now becomes destined become a neuron fly along the slightest
14:25 its final destination. Uh So some remain radio glial cells. But due
14:34 this asymmetrical cell division, you now a new subtype of the cell that
14:40 permanently destined to be a neuron. their precursor cells, these radial wal
14:47 , when we earlier saw them being as lattices, their cytoplasm continues.
14:53 it's one envelope of the membrane on cells where wheel cells and and neuronal
15:02 right here and then eventually they separate . So the birth of new neurons
15:11 versus asymmetrical. So, and what the faith of different subtype of
15:19 And that is the transcription factors. transcription factors, they can transcribe,
15:29 is DNA, which means they can on. The fact is to turn
15:35 a message in the DNA to express that message is then going to code
15:41 going to produce a message, that is going to become a protein from
15:46 uh uh uh a molecule of So if you have the cleavage
15:52 in this case, you have the Backus notch and no, and you
15:56 see that they're sort of like separated the cell almost in the north pole
16:01 south pole. So if you have symmetrical division, that means that the
16:08 daughter cells are gonna have the exact replica of these transcription factors. And
16:18 , they're gonna be the same time self. In this situation. The
16:28 cleavage plane is asymmetrical. What happens that one of these daughter cells is
16:38 dominated, the other one is non and now they're different. So if
16:46 divide, if you divide this the transcription factor, which is the
16:54 of the DNA code. If you it, mirror images, symmetrical cells
17:00 be the same. If you divide asymmetrically, you will have different
17:08 This is one of the coolest stories your book act actually. And I
17:16 put in a youtube video that we're to watch and it's called something.
17:21 title is not here, it's in book but how we kind of uh
17:25 oh yeah, there it is neurogenesis adult humans are how neuroscientists learn to
17:31 the bomb, the nuclear bomb in case. So let's uh let's read
17:42 this a little bit. So, believe that neurogenesis generation of new neurons
17:47 restricted to early brain development. But findings have challenged the student. Now
17:52 is that new neurons are continuously generated neural of developed brain, right?
17:57 question is we have the sy stem , the precursors that live in these
18:04 zones around the ventricles. That's what call ventricular zones. Do we have
18:09 in adult brains? Is this a feature of fetal or early adult,
18:16 postnatal or adult early development. There's more stem cells, there's no more
18:23 of new neurons in adults. So cell division requires the synthesis of DNA
18:27 can be detected by feeding the South's labeled DNA precursor molecules. Cells undergo
18:34 at the time the precursor is incorporate the chemical label into the DNA
18:40 the mid eighties. Uh not a of Rockefeller used this approach to prove
18:44 new neurons are generated in the brains the adult canaries, particularly in regions
18:49 with the song learning. So this a very interesting system in general who
18:55 verbs? I love birds. I listening to birds. Uh in my
19:01 , we have a lot of birds Dubai and they're really cool because they
19:06 these songs and the songs have been really well. And different birds will
19:10 different songs, you can hear different like and they'll repeat it and then
19:17 will enter a different song. So bird can have like multiple songs that
19:22 sing the different location. And this interesting because it's a very active
19:28 Uh And so this area contains uh cells, a finding resurrected interest in
19:34 double neurogenesis in mammals who had actually been described in 1965 by Joseph Alma
19:41 called Dasa mit research in the past years by Fred Gauge at Salt Institute
19:46 established definitively that new neurons are generated adult rat hippocampus. The campus is
19:54 special. It's a three layer So very interesting changes are happening
20:00 It has stem cells. It's really the structure important for learning and memory
20:05 therefore you're forming new memories, you're things, you need new cellular substrates
20:12 it. You need new cell, you need to regenerate some things that
20:16 lost. So uh the number of goes up in this region. If
20:23 animal is exposed to enriched environment filled toys and playmates. In addition,
20:29 , given the chance to have a run on an exercise, we will
20:33 enhanced neurogenesis. In both cases. increased number of neurons correlates with enhanced
20:39 and memory tasks that require uh the that require the hippocampus. So what's
20:47 on here? So they see that are stem cells, they find them
20:52 hippocampus and they let these mice run when they run, they have more
21:00 cells and when they have enriched environments other makes in the cage, rather
21:06 sitting in a, you know, cage by themselves or rat, they
21:12 more stem cells. Does that tell to tell you these activities and social
21:18 even for a rat is important to stem cells? So this is really
21:28 and so very recently. However, has been unclear, neurogenesis also continues
21:33 adult human brain, human brain, ? We found it in rats and
21:39 . So we like rats. So gonna have the same rules with stem
21:43 and genesis as rat hip camps will exactly rat. So definitive answer was
21:49 obtained by the analysis of an experiment several governments most prominent in the US
21:54 the Soviet Union formed in the world's during the Cold War. In the
21:59 between 55 and 63 hundreds of nuclear were decorated in atmospheric tests causing the
22:06 bread widespread dissemination of radioactive fallout. molecules basically levels of this radioactive isotope
22:16 14 was so high that it incorporated all the things including the replicating DNA
22:23 human neurons. So this radioactivity put a time stamp on every cell born
22:30 the bomb falls. This inspired by findings in rodents. Uh other scientists
22:36 their colleagues working at the Kolinsky in developed methods to detect this carbon
22:43 The neurons of human postmortem bras discovered neurons of the neocortex, whereas all
22:48 individual meaning no new cells had been in adults consistent with the dark.
22:54 while the data showed that hippocampal neurons continuously generated across lifespan. According to
23:01 calculations in the adult brain, about neurons are added to the camps every
23:06 . About as many are also Keeping the total number of neurons about
23:11 same. The annual turnover rate is 2%. And it says your hippocampus
23:18 not the same, your hippocampus had year ago. And uh that means
23:26 in 50 years, you have turned your hippocampus 2% times 50 you have
23:34 over neurons in your hippocampus. Maybe why things start going south after 50
23:41 you know, you already have done once now. It's like it's a
23:44 if you try to do it you know, OK. So that
23:48 really, really cool. Like how , right? This nuclear bomb
23:54 precipitation of radioactive material incorporates itself in . And then in Sweden, you
24:01 , they go and, and find human brain slice them, analyze them
24:06 , and show definitively that, that no in the, in the
24:11 is the same, but there would be new neurons in hippocampus. So
24:17 is a little bit of, of hope. Um And uh
24:25 I've actually uh have a video for to watch. It's a, it's
24:34 TED talk and it's, it's really cool. It, it takes
24:40 about 15 seconds to catch on to doctor Thet's accent. But uh can
25:03 as adults grow new nerve cells? still some confusion about that question as
25:10 is a fairly new field of For example, I was talking to
25:15 of my colleague Robert who is an and he was telling me,
25:20 this is puzzling some of my patients have been told they are cured over
25:26 , still develop symptoms of depression. I responded to him. Well,
25:31 my point of view, that makes the drug you give to your patients
25:35 stops the cancer cells multiplying also stop newborn neurons being generated in their
25:43 And then Robert looked at me like was crazy and said, but
25:47 these are adult patients, adults do grow new nerve cells. And much
25:53 his surprise. I said, actually, we do and this is
25:58 phenomenon that we call neurogenesis. One the underrated, hardest parts of being
26:04 youtuber is doing a ton of I'm constantly writing scripts. So now
26:11 is not a neuroscientist. And when went to medical school, he was
26:16 taught what we know now that the brain can generate new nerve cells.
26:23 Robert, you know, being a doctor is wanted to come to my
26:29 to understand a little bit better the and I took him for tour of
26:36 of the most exciting parts of the when it comes to neurogenesis and this
26:41 the hippocampus. So this is this structure in the center of the
26:47 And what we know since already very is that this is important for learning
26:52 memory and mood and emotion. what we have learned more recently is
26:59 this is one of the unique structure the adult brain where new neurons can
27:05 generated. And if we slice through hippocampus and zoom in what you actually
27:11 here in blue is a newborn neuron an adult mouse brain. So when
27:19 comes to human brain, my Jonas Friesen from the Karina Institute has
27:26 that we produce 700 new neurons per in the hippocampus. So you might
27:34 this is not much according to the of neurons we have. But by
27:38 time we will turn 50 we will all exchanged the neuron we were born
27:44 in that structure with adult born So why are these new neurons important
27:53 what are their functions? So first know that very important for learning and
27:59 . And in the lab, we shown that if we block the ability
28:02 the adult brain to produce new neuron the hippocampus, then we block certain
28:08 abilities. And this is especially new true for spatial um recognition. So
28:17 how you navigate your way in the . So we are still learning a
28:22 and they are not only important for capacity but also for the quality of
28:27 memory. And they will have been to add time about memory and they
28:32 help differentiate very similar memory. Like do you find your bike that you
28:39 at the station every day in the area? But in a slightly different
28:46 and more interesting to my colleague, is the research we have been
28:51 you know, what happens if you find your bike? Have you guys
28:56 of you been to Amsterdam? So is really what it looks like.
29:00 is not a joke. You come the central station in Amsterdam, you
29:04 see a sea of thousands of So what happens if you don't find
29:13 ? A lot of them are actually locked. And so people what they
29:19 is they, they just, you , look for 1520 minutes, they
29:22 find the bike. So they take logged bike the following day, they
29:26 it back there in the hopes that took their bike will bring it back
29:30 also. So they have another go it. But that is, that
29:34 a real thing, right? And like good luck. You know,
29:36 bike is somewhere there, you and you park at the station every
29:41 in the same area, but in slightly different position. And more interesting
29:47 my colleague, Robert is the research have been doing on neurogenesis and
29:53 So in animal model of depression, have seen that they have a lower
29:58 of neurogenesis. And if we give , then we increase the production of
30:04 newborn neurons and we decrease the symptoms depression, establishing a clear link between
30:12 and depression. But moreover, if just block neurogenesis, then you block
30:20 efficacy of the antidepressants. So by , Robert had understood that very likely
30:26 patients were suffering of depression even after cured of cancer because the cancer drug
30:33 stopped the newborn neuron to be generated it will take time to generate new
30:39 that reach a normal functions. So , now we think we have enough
30:48 to say that neurogenesis is a target choice if we want to improve memory
30:54 or mood or even prevent the decline with aging or associated with stress.
31:02 the next question is, can we neurogenesis? The answer is yes.
31:08 we are going to do now a quiz. So I'm going to give
31:13 a set of behavior and activity. you tell me if you think they
31:17 increase neurogenesis or if they will decrease . Are we ready? Ok.
31:25 go. So what about learning Yes. So what do you guys
31:33 learning increases, learning will increase the of these new neurons. How about
31:41 ? Yes, stress will decrease the of new neurons, hippocampus. How
31:46 sleep deprivation? Indeed, it will neurogenesis. How about sex?
31:54 wow. Yes, you are It will increase the production of new
32:00 . However, we will, it's about balance here. We don't want
32:03 fall in a situation about too much leading to sleep deprivations. So how
32:14 getting older? So, neurogenesis rate decrease as we get older, but
32:22 is still occurring. And then how about running Dell technologies smart infrastructure
32:29 by Intel Zion is staying ahead of workload, demands and anticipating security
32:34 empowering scientists with valuable data insights to conserve coral reefs for years to
32:43 So I will let you judge that by yourself. So this is one
32:48 the first study that was carried out one of my mentor Rusty Gauge from
32:52 Z Institute showing that the environment can an impact on the production of new
32:57 . And here you see a section the hippocampus of a mouse that had
33:02 running within its cage. And the black dots you see are actually new
33:07 neurons to be. And now you a section of the hippocampus of a
33:14 that had a running weight in its . So you see the massive increase
33:18 the black dots representing the new neurons be. So, activity impacts on
33:25 , but that's not all what you will have an effect on the production
33:30 new neurons in the hippocampus. So we have a sample of diet on
33:36 that have been shown to have efficacy I'm just going to point a few
33:41 uh to you. So calorie restriction 20 to 30% will increase neurogenesis,
33:48 fasting. So, spacing the time your meal will increase neurogenesis. Intake
33:54 flavonoid which is contained in dark chocolate blueberry will increase neurogenesis. Omega three
34:01 acids present in fatty fish like salmon increase the production of these new
34:06 Conversely, a diet rich in high fat will have a negative impact on
34:13 genesis. Ethanol intake of alcohol will neurogenesis. However, not everything is
34:22 , resveratrol, which is contained in wine has been shown to promote the
34:27 of these new neurons. So next you are at a dinner party,
34:31 might want to reach for this possible , neutral drink at the dinner
34:37 And then finally let me point out last one, a quirky one.
34:41 Japanese groups are fascinated about food textures they have shown that actually soft diet
34:49 neurogenesis as opposed to food that require , chewing or crunchy food. So
34:56 of this data where we need to at the cellular level have been generating
35:02 animal model. But these diets have been given to human participants. And
35:09 we could see is that the diet memory and mood in the same direction
35:16 it modulates neurogenesis, such as calorie will improve memory capacity. Was high
35:24 diet will exacerbate symptoms of depression as to omega three fatty acid, which
35:30 neurogenesis and also help to decrease the of depression. So we think that
35:39 effect on of diet on mental health memory and mood is actually mediated by
35:47 production of the new neuron in the . And it's not only what you
35:52 , but it's also the texture of food when you eat it and how
35:56 of it you eat on our Neuroscientists interested in neurogenesis. We need
36:03 understand better the function of these new and how we can control their survival
36:10 their production. We also need to a way how to protect the neurogenesis
36:15 Robert's patients. And on your I leave you in charge with your
36:21 . Thank you. Fantastic research on . Now, I told you,
36:31 changed my life. I now eat lot of blueberries. Um, I'm
36:37 interested in the running thing. Do I have to run?
36:42 Or is it really just about aerobic ? Getting oxygen to the brain?
36:47 it be any kind of vigorous So, for the moment, we
36:52 really say if it's just, you , the running itself, but we
36:55 that anything that in, in indeed increase the production, uh, of
37:00 , or moving the blood flow to brain, you know, should be
37:05 , right? So I don't have get a running wheel in my
37:07 No, you don't. Relief. . That's wonderful. So, thank
37:12 so much. You Margaret. Thank . Who knew? Right. And
37:32 really interesting, right? Especially the patient because that's a, that's a
37:36 problem. And whenever we do like for uh terminal diseases or severe diseases
37:44 that, we rarely look at what does to neurogenesis. As long as
37:51 kind of, it doesn't fill the and help somebody. It's OK.
37:55 that's important. Another thing is what does that mean? If you
37:58 antidepressants and you increase neurogen, what we learned about antidepressant drugs? What
38:07 , what neurotransmitters, what pathways do target? So I told, so
38:14 that mean that serotonin signaling or mean is an important component of almost like
38:23 the production of new neurons. It's in that because that's what the uh
38:30 do. They increase the availability of . And it's indeed, you
38:35 mono means are involved in the guidance neurons and their migration and patterning.
38:43 is really important. Maybe it's also in the actual creation of uh new
38:49 cells. So disorders on the other of the spectrum books that they,
39:00 are happiest. Yeah, they have maybe excess of serotonin. Maybe
39:10 have a slightly different wiring too. maybe not everybody has 700 new
39:20 I think 700 is probably an average they derived and, but some of
39:27 , you know, will probably lose ability to regenerate their cells and sooner
39:32 later. And that's all depending on these other factors that she talked
39:39 We stop. So. Hm. . Yeah. Yeah, it's an
39:49 on hippocampus. So, so why the question also? Why only in
39:57 ? Right? Why, why, nowhere else? OK. There
40:09 there we go. So it's an that simulates a venture calls. So
40:15 , that's like, I don't, don't, I don't think so.
40:19 you have an idea associated with Learning is obviously a big throughout your
40:29 . Whereas to take a motor the way that you use your muscles
40:36 really change that much over the course your life. So you don't want
40:41 change the way that your uh your system is wired. But if you
40:48 to, to keep constantly learning and need to keep recycling guns. So
40:55 best all those memories and all the that you need right now. And
41:01 would add to that. It's a interpretation. I would add to
41:04 that what you learn in the next of lectures is a function of hippocampus
41:09 not only encoding the new information or the new information, but also recalling
41:20 and, and it is and, I think you are, you are
41:24 because it's it has such an important . So even for example, memories
41:28 are learned, they're stored everywhere in brain, hippocampus is not the site
41:34 memory storage. Yeah. So ex time I know that you have a
41:49 of possibility. Oh yeah, it's music like different level of skills,
42:02 phones. So it's not just uh it's encoding the new patterns. Sir
42:13 would be more of an output and, and, and the actual
42:18 but the pattern learning will be more the cerebral cortex and memorizing that or
42:24 it will be involved in hippocampus. there's still iii I think that you
42:33 teach your muscles different things too. know, they, they, they
42:38 learn different things too. Sometimes you to the gym and if you have
42:43 routine of using like five or six machines and then you come in the
42:48 day and you use completely five different , you walk out of the gym
42:52 , oh my God, what is ? Like, what, what is
42:55 muscle like? I didn't know it . I'm not saying that being sore
42:59 , and, and training it is , is a different, uh,
43:03 don't know, way of interpreting but that's, that's an important way
43:08 think about this. Why, why , why this area? I know
43:14 , that he said that he but all that, but exercise or
43:23 activity or in, or dentist specific that about running the, the,
43:33 reason why they originally said it's only is because, yeah, it
43:39 it was rodents and they put them the wheel. So they run and
43:45 humor. Well, that's how she it. I think that what they're
43:50 is increased physical activity that uh, and exchanges the blood in the
43:57 Yeah. Yeah. But originally it with running because they put the
44:02 the rat gets in the wheel, it runs and it was an easy
44:06 to count how long it runs, much the wheel spins and then look
44:10 the number of neurons because otherwise if do some other activity, you have
44:15 track them and what kind of activity they doing? You know? But
44:19 don't know what other exercise rats can . Like they kind of lift,
44:24 know? I mean, so, . Ok. So while when the
44:33 neurons are born, now these neurons to have to migrate and uh they
44:40 to migrate. So this is really if you look like this is the
44:47 . This is these ventricular uh the zones along the ventricle with the new
44:53 are more. So you have origin o oligo denro size and this is
44:56 the ventral side, you have galic the neurons and that's sort of a
45:02 between, but it's still on the side and then the birth of parameter
45:11 is right here on the dorsal So first of all, there is
45:17 differentiation when you have the formation of cells, there's a formation of
45:23 then there is a formation of astrocytes , the formation of neurons uh then
45:29 have other cells like the Ligo And it tells you that it's pretty
45:36 for petal cells that are born right . Just use that migration lattice and
45:43 precursor cells are just poop, just up a layer or two or three
45:48 . So the distance here is pretty . However, if you look at
45:51 distance for this into neuron or Ligo , it actually has to travel a
45:57 of times it's quite a far distance young brains, that distance is just
46:02 couple of centimeters. It's not that as it is in adult brains,
46:07 still you have quite a ways in or lid denys and they have to
46:14 laterally along the cortex or they migrate the color of their fashion. And
46:25 themselves within the cortical structure. So not gonna read through this uh making
46:35 off the mind back of discovery. when I first showed you this beautiful
46:43 , uh they on climbing around along Wheel Cell, it took so long
46:49 . And when they say originally, was done in the late sixties and
46:56 . So there was no way to understand how this process is happening.
47:01 Professor Pasco Rakic, he is a . Uh he's really the person that's
47:09 as a stated hero with 50 years his life now into understanding the pattern
47:16 and the cortical pattern formation. And us to visualize this image because this
47:22 basically shows this uh ventricular zone, have sub ventricular zone and then going
47:30 the cortical plate. So this is neurons are going to migrate in different
47:36 in the cortex. But to generate image, this is like thousands of
47:42 microscope images that are being placed in three dimensional stack. So when you
47:48 that image of the seventies, roll unbelievable though. Now we're seeing movies
47:54 a lot more resolution. But it , it took somebody um a lot
48:00 time and at that time, they didn't even have powerful enough microscopes
48:05 the university. So they had to with NASA in order to visualize some
48:10 these details and use NASA micros. uh Doctor Rae also came up with
48:22 really uh interesting uh theory and it like it is probably true. So
48:33 is the ventricular zone, the sub zone, these are the results where
48:37 are more. And there's two important in here. First of all,
48:43 think that what's happening here at the zone, it's like a movie,
48:52 ventricular, these radial glial almost posts OK. From these developing cells.
48:59 . You have the MN which stands migrating neural precursor. We have RG
49:05 is rad glial cell and it seems in this ventricular zone, there's this
49:13 that had been created and that movie projected into the cortical play into the
49:23 . And there is another, let's . I don't think I have the
49:35 um mentioned in here. So why I say it's, it's like a
49:41 . Uh So there's an experiment, I include that? Maybe it
49:52 There was an experiment that was done the cortex, occipital cortex was substituted
50:02 some have a san cortex. So literally move with the somatosensory cortex into
50:11 cortex underneath the region where these projections going. And the cells go into
50:18 somatosensory cortex and formed the barrel cortex they have in rodents about a sensory
50:26 . So I did have this actually a text but it's much further.
50:34 no, I didn't. Yeah. , something about a movie. Where
50:44 it? Yeah, the movie can displayed over many different devices or projector
50:55 . So what's going on here? the code is the movie here.
50:59 the code is here from these precursor from these radio glial cells. And
51:04 interestingly, they're gonna drive this one glial unit is going to drive the
51:11 of these micro calls and cortex. these guides in this area of ventricular
51:17 have a code for occipital cortical column . These guys over here have a
51:24 for Samantha sensory column here. If substitute the tissues, they still grow
51:30 each other. So the movie is , the movie is there. But
51:34 come the movie can be played on or not there? So the cortical
51:41 is like a different screen. The is here and you project this structure
51:48 the screen which is your cortex, you physically project it. That means
51:53 these neurons in the movie has the to be projected on multiple different
52:00 potentially using similar or different devices for example. So that to the
52:13 level, it's almost like a something is almost coded in two dimensions here
52:22 one line continues and forms this three structure along the along the same
52:30 So each micro column movement had its major guiding radio glial sets, a
52:39 of them and some of them will radial glial because they're radial glial,
52:44 dividing symmetrically and some of them turn symmetrical into neurons and and have these
52:52 migrate in and fill in the movie the onto the screen. This is
52:59 a movie that's being projected onto the . They connected physically 1.1 or is
53:12 that it's a specific pathway and they're connected within the column? And actually
53:19 later, the first c will you see in the subsequent slides person had
53:23 654, I guess when they become connected when they get to 23,
53:31 when they start getting connected in So at first is this movie,
53:35 like going into the tube, it's here until it climbs all the way
53:40 the top layers. Then it starts in between. Uh it shows here
53:49 example, some abbreviations, thalamic radiations says monoamine inputs. So monoamine inputs
54:01 nucleus masalas, a meaner inputs, that we talked about is important in
54:07 process. Second time it's showing up years, antidepressants potential ssris here is
54:16 the cell migration. Just a reminder the structure of cerebral cortex. It
54:24 L structure you can reveal with it has polymer structure, you can
54:30 with bulgy stain wider stain, it axons and we will have different
54:37 Different structure of sport exists above and one of these micro columns is like
54:45 local processing unit until they start being into more coherent picture from individual processing
54:54 . This is the cell migration. first step as happens, it goes
54:59 this ventricular zone to me zone in subway, the subway zone is right
55:05 layer six and eventually it actually disappears longer here of sub la it goes
55:12 cortical plate into this cortical plate. marginal zone you heard first have in
55:18 of layer six nerv of layers And finally, you have innovation of
55:26 upper layers here 23 and this is development of progression of these development.
55:32 you first fill, fill the deep and then the last you'll fill the
55:37 superficial layers. And that's where most the lateral connectivity and communication between cells
55:45 . So it's sort of an inside from inside of the deep layer,
55:53 you have differentiation. So first, I said, you'll have differentiation of
55:58 and you'll have differentiation of exercises, differentiations, other uh we all surprise
56:04 the good under size and so But first, it's sort of a
56:09 and it's just a blob really with nucleus. And after a while it
56:14 showing its processes uh elongation. Um again seems to be programmed although it
56:23 dependent on the chemo attractive chemo meaning where these uh are going to
56:30 north or south, east and west then the formation of this state.
56:35 of all, the axonal formation and is sort of a will be fueling
56:41 around where it needs to establish the . And then later the formation of
56:46 we typically know about the parameter cell the basal dendrites at the base and
56:51 the optical dendrites at the apex of parameter cell. Uh So it
56:59 this happens after it reaches its So first it it becomes a
57:05 it's a neuron, but it's a of a neuroblast. And as it
57:10 up, that radial glial cell that off, let's say in layer
57:16 Now it's going to differentiate into graal or it's going to differentiate into an
57:23 into neuron or another subtype of And this is dependent on this summer
57:31 three A. So we'll talk about molecules and also transcription factors. So
57:37 like chemo attractants, chemo repellent trophic that influence the growth and for which
57:44 and neuro ad growth will be competing . Um So again, high,
57:50 of foreign area will influence the formation these dendrites and dendritic branches.
57:56 some of foreign area will influence this or less elongated um axon.
58:06 neurons are differentiating into neurons but areas the brain are also differentiating into specific
58:14 . So in this example, here have B which stands for visual
58:19 A for auditory sence amount of sensory M for motor. So this is
58:25 rough cartoon like representation that you have patchwork uh kilt that we call.
58:34 each square of that kilt is like little patch and it's responsible for its
58:39 function motor sensory and so on. the the other way that we understand
58:47 this patterning of the cortical areas happens first of all this radial unit
58:56 So this is radial unit hypothesis that to this, that there is a
59:01 unit that has a movie and that muda uh radio uh uh real movie
59:09 going to be projected as a as cortical structure. So some neurons migrate
59:22 . So once they get to certain , they may migrate laterally. It's
59:26 all within the column. And thalamic contributes to this cortical differentiation. But
59:34 general, the other thing that contributes uh these genetic expression of certain
59:41 And if you look at the developing , you have two molecules pack six
59:47 EMX two. Again, they can transcription factors, pack six is dominating
59:54 rostral and EMX to the caudal part the brain. This is an experiment
60:00 which you have a wild time And in this case, you knocked
60:06 EMX two. So you have a EMX two. Everybody knows what a
60:12 is. You eliminate that gene. you eliminate EMX two, you eliminated
60:17 dorsal portion. And all of a , a lot more neurons are actually
60:24 into the PAC six area. And you knock out pack six, it's
60:30 opposite. A lot of the neurons now expanding into that visual area into
60:39 area. So that tells you that is a differential expression of molecules
60:48 And in part, these will serve the influencers to wear specific cells and
60:57 much of these cells for? So you think we all have the exact
61:04 precise pattern and gradient of pack six EMX two as individuals? That's why
61:12 individuals because we don't, that's why some of us are more talented with
61:18 motor. So the visual or so a sensory and that is again a
61:26 of the code and potentially the But in most instances, it's it's
61:31 code and the nurture inside the fetus , and and and in human brains
61:36 particular. So you have these molecules you have to have thalamic input in
61:44 to generate and to differentiate the cortical correctly. Now, this is an
61:52 of where you have normal cortex that can see very clearly, very pronounced
62:00 matter density, certain densities of layers the South. And here there was
62:06 LGM input. And what happens is this primary cortex, visual cortex is
62:13 shrunken and it has changed its CTO . This is the experiment that I
62:22 earlier that, that, that this basically c architecture differentiation cortical area where
62:28 replace different patch of cortex. The why I put it here is because
62:34 is really interesting. So LGM contributes this patterning of the cortex as if
62:41 movie can be displayed over many different or projector types. And also that
62:47 is now influenced by thalamic inputs and influenced by uh mono mener inputs in
62:55 to, to create that movie. yeah, if you eliminate sensor
63:00 if you eliminate LGM input into cortex doesn't form the same way.
63:09 so we have three things. First all, you have the pathway selections
63:13 these uh retinal gang in axons that coming out, they will come to
63:19 eye as and they'll have to decide go back in. Do they go
63:23 the right? Do they go to left? They go into this eye
63:26 and they decide that they're going to to the left. So that's the
63:31 selection. And that means that there's of this cross that is gonna influence
63:36 fibers to cross over and temporal fibers stay the same. And we'll look
63:42 some of this patterning. I'm, think I'm gonna run out of time
63:45 . We'll look at it next, lecture. So that's the the path
63:50 the target selection. This optic track going to go into the lot of
63:59 , that's the target, but it going to go into the thalamus and
64:06 contains other nuclei. So here it's medial nuclear nucleus and it's going to
64:14 , oh, that's not the pathway me. OK. My target is
64:20 here. My target selection is LGM not interested in the GM. I'm
64:26 to LGM, the auditorium was are do something different. They're gonna go
64:30 MGM, they're gonna say no to . Finally, the address selection and
64:37 reason why I say the address selection because once you come up to the
64:45 , you have to select your Is it, are you layer two
64:50 you layer three, are you in middle of this layer two on the
64:55 the dorsal side, are you on middle, closer to midline on the
65:03 side? And when we look at like this, there's probably a lot
65:10 detail. A lot more of that is already present here. And we
65:15 don't understand if the actual pattern of and how they distributed within each individual
65:22 . It is really interesting and uh destri cortex, we already talked about
65:32 . Why did it come back to out? Because I jumped over slides
65:35 it's like what again? OK. I think we're gonna end here.
65:39 we're going to discuss next lectures how are growing. Why axons don't regenerate
65:47 about external guiding? We're gonna start about these retinal topical maps. So
65:53 text and projection. So we'll start why certain fibers will go its
66:00 other fibers will stick onto the lateral then move into the second section of
66:05 the brain which is going to be to some plasticity. Already. Any
66:11 on this. All right, good discussion. Keep thinking about the
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