Welcome back to medical neuroscience, and welcome to this tutorial on the

Modification of Neural Circuits in Early Neonatal Life.

Our core concepts that pertain to this session are first of all that life

experience effects the function and the structure of the nervous system.

This is really the whole point of this discussion today, is to talk about how

sensory motor experience changes the nervous system.

Well, for me anyway, this topic certainly pertains to one of our core concepts in

neuroscience. And that is that our human brain is what

endows us with a natural curiosity to understand how the world works.

And this has been the case for myself. what I'll be speaking to you about today

pertains in part to some research work that my colleagues and myself have

undertaken over the last decade or so. So, for me, this certainly is a topic

that is born from my own sense of curiosity.

And of course, I have my brain to thank for that.

And then, lastly, this topic that we will discuss today is going to be largely one

that will relate to primary research discovery.

And it's certainly my hope, as a neuroscientist that fundamental

discoveries will continue to promote healthy living and the treatment of

disease. And one of the really fun things about

neuroscience discovery is that often basic neuroscience discovery can lead to

innovation in the treatment of the human condition in ways that we might not

expect as basic neuroscientists. So I think that one is never quite sure

where significant application and translation will come from as long as we

continue to pursue our curiosity and continue to pursue basic discovery.

And whatever domain of science you may be involved in.

And for me that's especially exciting to be involved in the ever expanding field

of neuroscience. Our learning objectives today are first,

that I want you to be able to discuss the significance of genetic specification,

self organization, and sensory motor experience for the construction of neural

circuits in the cerebral cortex. I want you to be able to discuss the

significance of experience for the plasticity of neural circuits during what

we'll call critical periods of postnatal development.

And lastly, I want you to be able to return to a concept that we discussed way

back in unit two of the course. And that is Hebb's postulate.

And I want you to be able to discuss the relevance of Hebb's postulate for

understanding developmental plasticity. Well I'd like to start our discussion

today as I have the last couple of sessions.

And that is by providing a broad overview about the major forces that are shaping

brain development. Now, as I think you've been able to

appreciate so far, these forces interact with one another.

And they do so with one theme perhaps dominating at a different stage of

development more so than the others. Obviously, sensorimotor experience

doesn't become relevant until neural networks are functioning and begin to be

modulated by the interaction of the developing child with the outside world.

so sensorimotor experience is an influence that is emerging in brain

development relatively late in the process.

Nevertheless, it is an important factor. And what we want to consider today is

really when does sensorimotor experience become a major force in brain

development? And how does that force interact with

these other two genetic specification and self-organization.

Well, just to refresh your understanding of these concepts, genetic specification

refers to lineage derived factors that reflect the spatial and temporal patterns

of gene expression. So perhaps it's convenient to think of

this as, as nature, that is a reflection of the genetic constructions.

That each cell in the nervous system inhered from its parent cell.

Well, self organization is a relatively under appreciated concept I would

suggest. Self organization reflects the dynamical

behavior of neural systems once synaptic connectivity is established and becomes

functional. And self-organization reflects cell to

cell interactions that are mediated in an activity-dependent fashion.

And I'll, I'll emphasize activity to describe self-organization rather than

experience because much of the activity in the nervous system is generated

endogenously. That is, it is ongoing.

It doesn't require external drive to generate that activity.

And this endogenous activity provides the sub stratum if you will, for self

organization to play itself out. And we'll see a powerful example of that

today. Well sensorimotor experience becomes

possible relatively later in the story of early brain development as neural systems

begin to transduce electrical and chemical and mechanical information.

That might be present as the developing fetus and developing infant begin to

interact with the external environment. And these interactions then produce

electrical signals that are driven from external sources and have the capacity

then to modulate these ongoing patterns of activity.

And all of these factors genetic specification experience,

self-organization. They interact in complex ways that we

still don't quite understand. And the result is the coordinated

development of a nervous system that becomes progressively attuned in order to

experience the world and respond with appropriate behavior.

In this remains much of the challenge of modern neuroscience to understand exactly

how this happens. So what I would like to do for much of

this tutorial today is to really focus on what we might call nurture.

That is sensorimotor experience. The environmental interactions that begin

to shape. the epigenetics that can modulate genetic

specification. And, and also, those modifications that

potentially can have a role to play in shaping the outcome of self-organization.

So I want us to consider the contribution of sensory motor experience to brain

development by focusing in on one key sensory system.

That has served as one of the principal models for understanding these forces in

early brain development. And that model system is the visual

system. And I'm going to break this down into

really two principle parts. One part will pertain to those properties

that are present as the thalamus first supplies inputs to the middle layers of

the cerebral cortex. So in this case we're talking about

inputs from the lateral geniculate nucleus that are terminating in cortical

layer 4. Now, you'll recall as we've talked about

now since the beginning of Unit 3 that one of the principle architectural

features of the cerebral is a columnar circuit.

That repeats many, many times across a cortical area.

And, we think that that columnar circuit serves at least three important functions

that I've suggested you remember by recalling the ACC of the cortical

microcircuit. the first function that's performed by

the circuity is amplification, and that's principally amplification of this

thalamic input. So these inputs are processed among small

cells that we call stellate cells in cortical layer 4.

And from there the information is passed on up into the upper layers of the

cortex. And from there, down to lower layers of

the cortex. So there's sort of a recurrent columnar

circuit that amplifies the input that is received in the middle layers of the

cortex. We'll go on and talk about the

computation of the new cortical properties in the next part of this

tutorial. So what I'd like to talk about in this

first part of the tutorial are the forces that shape.

The initial topographic mapping of this thalamic input into cortical layer 4.

And just to give you a sense of what the outcome of a long series of experiments

suggests is that there is an early to phase to the development of this system.

That some have called a precritical phase, to emphasize the idea that this

phase establishes the basic mapping funciton that allows the thalamus to map

into layer 4 of the cortex. And it's precritical in the sense that it

doesn't seem to require. visual experience in this case, since we

will be talking about the visual cortex. Now, this implies then that there must be

a later phase that we'll call a critical phase or critical period, where sensory

experience, visual experience. Can indeed alter the structure and the

function of the circuits that are initially established as the thalamus

maps into layer 4. Well, as I mentioned we're going to be

talking about the visual cortex. just a little bit more background to

remind you of where we're going with this.

So the visual cortex. That we have in mind really is the

primary visual cortex, which is what we find in the banks of the calcarine sulcus

here. this is a beautiful image supplied by my

colleagues in our field of visual neuroscience.

Dr Daniel Adams and Jonathan Horton. this part of the brain is exquisitely

organized in so many different dimensions.

unfortunately, beyond the scope of our consideration in this course.

but it has captured the imagination and the attention of now, at least three

generations of neuroscientists who've been, studying this part of the brain.

It is undoubtedly the best understood region of the cerebral cortex.

So it serves as well as a paradigm for understanding some of the principal

forces that are shaping the development of the brain more generally.

Well, this cortex as you know, is topographically organized.

the fovea representation is found. At the occipital pole of the hemisphere.

And as one progresses from the posterior towards the anterior aspect of this

calcarine sulcus cortex. One moves from the central region of the

visual field, out towards more peripheral regions of the visual field.

And this beautiful color code as visual field is related to visual cortex reminds

us of this orderly progression of visual typography.

It also highlights the fact that what's most important to us in vision Is

represented by nearly half of the visual cortex.

And that is the central ten degrees or so of the visual world.

So it's really, the representatives of the fovea.

And surrounding the fovea, the macula. And then the, the, nearby regions of the

retina that account for much of the detail that captures our visual interest.

And this is represented by circuitry that spans about half of the visual cortex.

That's not to say that what happens in the periphery isn't sill relevant for

visually guided behavior, of course it is.

But it doesn't require as much circuitry to analyze the details of form and color

and location. as what we find in the representation of

our macular region of the retinas. Now, just to remind you of what this

region of the brain actually looks like histologically speaking, here's our

calcarin sulcus that we see in a histological slide that's stained for the

presence of myelin. And on the superior bank of this

calcarine sulcus we have the cuneus gyrus, which is going to be representing

the contralateral inferior quadrant of visual space.

Whereas on the inferior bank, we have the lingual gyrus, which is representing the

contralateral superior quadrant of visual space.

Now this part of the brain is often called the striate cortex because of this

densely myelinated stripe of cortex that we see that runs right through the middle

layers. So while this, stripe is not precisely

layer four it`s found within layer four of the visual cortex.

So the first part of the story that I'd like to today about the formation of

topographic maps and how sensory experience can alter the structure and

function of those map. Really pertains to establishing the

initial connection from the thalamus to this region that's recognizable by this

heavily myelinated strippend visual cortex.

Now, you may recall that one interesting feature of this middle layer of the

visual cortex that was discovered back in the mid 60s to late 70s.

Is the system of ocular dominance columns that we find in the middle layer of the

visual cortex. So let me remind you about ocular

dominance. as you know, the two eyes are sending

signals into the same lateral geniculate nucleus.

But, as you'll recall, those signals are not yet combined level of the thalamus.

Rather, the two eyes project to separate layers of cells within the lateral

geniculate nucleus. The contralateral eye projects to layers

1, 4, and 6. Whereas the ipsilateral eye projects to

layers 2, 3, and 5. It's not yet until these circuits are

amplified at the level of the visual cortex, do the inputs that are driven

from the two eyes first become combined. And in fact, even in cortical layer 4,

there is still segregation of these inputs.

So, as the thalamus projects into cortical layer 4, there is initially a

termination of afferents that segregate very quickly into complimentary zones

such that one can progress across the visual cortex within layer 4.

And encounter these alternating bands or alternating columns if we think in the

radial dimension, that are driven primarily if not exclusively just by one

eye. Now, once we get above cortical layer 4

the inputs do become mixed. And so this means that stereopsis is

first possible in the upper layers of the visual cortex.

Where information from the two eyes begins to converge on the same cells for

the first time in the visual pathway. Nevertheless, even in the upper layers of

the visual cortex, there's still a bias towards information that's being driven

by one eye or the other. Well, this fact was not lost on David

Hubel and Torsten Wiesel as they discovered ocular dominance columns

together with their collaborators. such as Simon LeVay and Carla Shatz.

and what these individuals recognized is that, this system of ocular dominance

columns in the visual cortex presents a wonderful opportunity.

To begin to design experiments to look at the role of experience in early life.

Well what was especially powerful about this system is that not only could this

system be probed physiologically with microelectrode recordings.

And one could assess the degree to which one eye or the other was responsible for

driving the action potentials. Recorded from a neuron and anyone of

these ocular dominance columns. But there's also an anatomical correlate

that could be visualized through various means.

And I'd like to show you one other image. from my friends Dr Horton and Dr Adams.

And this is now one of my very favorite images in the entire field of

neuroscience. What we're looking at here is a photo

montage constructed from the human visual cortex.

And, this is tissue that has been prepared and stained to demonstrate the

presence of a oxidative enzyme that's found in mitocondria.

So to chromoxidase and so the intense dark brown regions are those regions that

have high levels of cytochromoxidase activity.

And the more pale regions are those with low levels of cytochromoxidase activity.

So, the intensity of the brown tells you something about how metabolically active

the individual locations in this cortex were in life.

Now this visual cortex was derived from an individual who passed away.

After having one eye removed. And as a consequence, the ocular

dominance columns or stripes in the visual cortex, that were driven by the

eye that was removed, had down regulated their oxidative metabolism.

And as a consequence. The columns that were driven by that eye

have now become much less metabolically active.

And hence we can reveal, for the very first time, the complete pattern of

ocular dominance columns in the human visual cortex.

Now take my word for it, this was a Herculean effort.

Very few histologists are skilled enough to have produced an image such as this.

what Dr Adams, and Dr Horton, and their staff were able to accomplish here is, is

truly a remarkable bit of anatomy and histology.

What they were able to do is to gently unfold the cortex of the occipital lobe

in the upper and lower banks of the calcarine sulcus.

To flatten out that cortex and then to produce sections through it that then

could be stained to demonstrate this metabolic activity.

And what we see is truly a remarkable picture of the structure of the human

visual cortex. I hope you're struck as I am by really

the beauty of this image. So what we're looking at is a

representation of visual cortex with the Posterior pole of the hemisphere, here to

left side of the image. The anterior side of the calcarine salcus

cortex to the right with the superior aspect, the cuneus gyrus above.

And the inferior aspect, the lingual gyrus below.

But really, the main feature for you to recognize is this beautiful pattern of

stripes and columns that we see. So these are indeed our ocular dominance

columns, or ocular dominance stripes as we might recognize them here in this

broad view of the visual cortex. So these dark regions are those that are

driven by the eye that remains. And the intervening pale zones are those

that were driven by the eye that is now removed.

And hence, they have down regulated their enzymatic activity.

Lessons from Studies of Ocular Dominance Columns, part 1

Medical Neuroscience

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