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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.
1:14
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.
4:35
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.
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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.
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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.
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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.