0:25
So, we would like to, to choose a circuit, some circuit, and reconstruct it
in details, anatomically, also physiologically.
Put all these things together under a modeling framework.
And simulate it in both health and disease, this particular network.
So the question is what, what, what, what should we choose, what network should we
choose? You already saw this little cartoon,
which I'm going to dwell about more just now.
Showing that if you look at the mammalian brain, the mammalian neocortex just below
your skull, you see that this neocortex is of course, built from neurons, from,
from many neurons. A lot of neurons, but if you look at the
skull, so this is the skull side, and this is deep inside the skull, about two
millimeters deep. Depth into the skull, you see these
layers and layers of cells. We will discuss these cells in a second,
we already said something about these cells just to give you a ballpark.
If you look in the cortical, in a cortical circuit of human, of mouse, of a
cat, of a monkey, doesn't really matter, you see somewhat similar things.
Of course, there are differences between one species to another.
But, in general, just to give you ballpark number, so if you look at the
cubic millimeter on the order of cubic millimeter.
Yes, from the surface deep inside. About two, two millimeter deep, one
millimeter this direction, and one millimeter into the board.
So about two, cubic millimeter, one cubic millimeter, you get on the order.
Again, there are some variations between species, on the order of let's say,
30,000 cells. Okay, so this is a, a chunk, this is a
piece of a brain. In the particular region, the cortical
column as well call it. We'll talk later about why is it a
column. But we can talk about the column that has
this size, and it has about 30,000 cells and maybe about 100 million connections
within this. And about 100 million synapses, it's a
huge number. Huge number of cells, huge number of
synapses. So, it's a rather big piece of a brain.
It's small relative to the whole brain but within itself it's, these are big
numbers. Looking at it differently, and actually
people looked at this. Long time ago, early anatomist,
including, including Ramon Y. Cajal and others, but they didn't call it
cortical column. They look at the brain, they thought it
maybe built from some kind of building blocks, maybe not.
And then they started to draw, people like the Hungarians, Santiago Ty and
other people related to cortex, trying to reconstruct pieces and trying to
understand the circuitry. The elements that build up this
particular circuitry in the cortex. So, I can bring you several nice
pictures, early pictures. Another one that is now classical, just
to give you a notion. A very, very rough, without details yet.
So this is the surface of the cortex. This is deep into the cortex about two
millimeters deep here. And you can see that there are many
different cell types. We discuss cell types.
Some of the cells are pyramidal cells, we discussed them.
Some of the cells are spiny stellar cells.
Some are inter-neurons. Some are inhibitory.
Some are excitatory. Many, many cell types within, a circuit
like this. And when I say type, we mentioned that
you can, classify neurons both by their anatomy, also by their physiology, also
by their synaptic properties, also by the genetic properties, there are many ways
to classify neurons, into types. So in this case of course I'm showing you
an anatomical type, because I don't show you activity here.
4:21
But you can see that there are these trees, different trees and different
types composing a network. And you can see also when you start to
study this network that this network receives an input okay, coming from these
blue axons, coming from elsewhere into the network from the thalamus into the
network. Or from other modestal regions and this
input is going to different layers. To different regions.
From the thalamus it mostly goes to layer four.
From other regions it mostly go to layer one and so forth.
And so you, you can start to make some kind of an order, some general order that
it's not all to all and not everybody is talking to everybody.
And the input doesn't go everywhere and so on.
In general there is some order, not that we understand all this ordering, but
there is some order. And so people in the last, I would say
hundred years, are starting to more and more, dwelling, learning, studying, this
particular network, because the cortex is something of course very interesting for
us, as mammalians, as humans, because in the cortex which is relative new in
evolution, about 200 million years old neocortex, this neocortex enabled the
mammalian world to generate new behaviors, including me, creating new
things maybe, help, with the help of my cortex, generating language, language and
so forth. Who knows what comes from this cortex,
it's relatively new in evolution, and, so, so, naturally we are interested in
that. And, so, there is a lot of study about
this cortex, and some of this studies, whatever we know, we would like to put
together, in this simulation based blue brain research.
For example, if you deeper into this cortex, this neocortex, this neocortex
below your skull, you can see that there are layers.
I already mentioned layers, but I didn't say what I mean by layers.
So, you can define layers in many ways. We think about six layers typically,
again this is only typical. Some regions have less, some regions have
more layers but say layer mean that the cell bodies of certain cells, it's dense.
You will see soon, in a second, the layering of the cortex.
You can think about layers. So this is some kind of order.
You make an order by saying I have layer here with cell bodies.
And dendrites emerging out and down. After down there is another layer, layer
five with cell bodies sitting here. I can, I can try to make some order in
this jungle but also speak about different cell types as I mentioned
before. So, this will be the blue dendrite of
layer five pyramidal cell and the blue axon.
Or the bluish axon here, will build layer five parameter cell axon.
You may subdivide layer five into two types, layer five a, layer five b, and so
forth. Though I don't want now of course to go
into elaborating into each type, but I, I'm trying to say that we are trying to
make an order with this piece and we know quite a lot about it.
7:32
We don't know also quite a lot about this, but we know a lot about these, cell
types and so, and so on, and recently because of new techniques new
technologies, you can see for example here, a column, or a cortex, with this
surface going down, and you can see dense cell bodies in layer two and cell dense
bodies, if you have good imagination you can see layer here less dense here, and
so forth. You can speak about layers.
So this would be layer six cells. This would be layer five cells.
This would be layer four and so on. Again this is you may, you may say don't
see exactly the layers. And so forth but I'm, I'm just showing
you that we are trying to make some anatomical order which has some
foundation because the input is not going everywhere.
Cell types are different in some sense from one layer to another.
And so we, we are trying to make order you can see and this order hopefully will
help us understand the function. Hopefully but this is only anatomical
order, and we also want to make other type of orders.
We also have today, beautiful, elaborate, intensive, really intensive work.
In this case from Kevin Martin lab trying to in details look at a particular cell
type. For example this cell.
Is the spiny cell itself. From cat v one, from the primary visual
cortex of the cat, in layer, in layer four, in this case layer four spiny cell
itself. And you can see, an attempt, to map out
all the synapses. The inputs into this particular cell.
So, for example, all the yellow dots, this dot, this dot, this dot, all the
yellow dots signify eh, an input coming from the thalamus.
So this is another region. Earlier region, in the visual system,
going into this cell, and making synapse here, here, here, here, all these yellow
dots. You can sink, you can think about all the
green dots, so here are the green dots, here is a green dot, here is a green,
another green dot, very hard maybe for you to see another green dot, another
green dot, many, many green dots. These green dots are coming from lateral
input from similar sets. So of course this is not the other spiny
stellate cells in this region. There are many many spiny stellate in
layer four and this spiny stellate cell talk to each other via axon in synopsis
so you can actually mark. Statistically at least where the inputs
from other nearby similar spiny stellate cells in pinged on you and so on.
So this is now a map at the level of single cell.
Of who, what is the synaptic environment around you?
What is the source of input? Who is the source of input?
Near you, from nearby cells, but also maybe from faraway cells.
From the thalmus, or from other, other regions.
So this is a synaptic mapping, a synaptic map, onto this cell, and you know now,
after the lesson we took before, that eventually all these synapses Together.
11:06
We don't know just by looking at it. We know the substra, the substance.
Who is talking to you, but who is talking well, and when he talks, what does he say
exactly? This doesn't give you.
So, it just gives you the map of synopsis with out any activity.
But this is a beginning of trying to decipher the activity of this particular
cell resulting from the activity of it's neighbors.
So, this, this is the thing we can do today.
And, there are of course, many, many, many other types of information I could
have shown you, that we are now starting to collect.
So, what I'm saying that we're trying to collect, to put together, all the
information available, I mean, the location of synapses.
The type of cells. Also the firing properties of this
particular cell. And, and, also the, the, the strength of
synapses, the type of synapses, is it inhibitory, is it excitatory, so as I
said we know some of this information, not all of this information, and
especially we don't know all this information while the animal behaves.
So I cannot tell you now, that when this cat, I don't know, looks at the, at the
orientation, oriented but this, and this, and this synapse will be active.
This, this I cannot tell you now. I can tell you, due to some results that
I mentioned last time, by our Arthur Conners and colleagues, whereby they can
record the input. They can record the activity of this
synapse or this synapse, while the animals viewing some relevant input, like
an oriented bar /g. But of course this is a static, this is a
static picture but it's the beginning of, of, of organization of data hopefully in
some systematic way we shall continue to talk about this in a second.
Idan SegevProfessor
