Medical Neuroscience explores the functional organization and neurophysiology of the human central nervous system, while providing a neurobiological framework for understanding human behavior. In this course, you will discover the organization of the neural systems in the brain and spinal cord that mediate sensation, motivate bodily action, and integrate sensorimotor signals with memory, emotion and related faculties of cognition. The overall goal of this course is to provide the foundation for understanding the impairments of sensation, action and cognition that accompany injury, disease or dysfunction in the central nervous system. The course will build upon knowledge acquired through prior studies of cell and molecular biology, general physiology and human anatomy, as we focus primarily on the central nervous system. This online course is designed to include all of the core concepts in neurophysiology and clinical neuroanatomy that would be presented in most first-year neuroscience courses in schools of medicine. However, there are some topics (e.g., biological psychiatry) and several learning experiences (e.g., hands-on brain dissection) that we provide in the corresponding course offered in the Duke University School of Medicine on campus that we are not attempting to reproduce in Medical Neuroscience online. Nevertheless, our aim is to faithfully present in scope and rigor a medical school caliber course experience. This course comprises six units of content organized into 12 weeks, with an additional week for a comprehensive final exam: - Unit 1 Neuroanatomy (weeks 1-2). This unit covers the surface anatomy of the human brain, its internal structure, and the overall organization of sensory and motor systems in the brainstem and spinal cord. - Unit 2 Neural signaling (weeks 3-4). This unit addresses the fundamental mechanisms of neuronal excitability, signal generation and propagation, synaptic transmission, post synaptic mechanisms of signal integration, and neural plasticity. - Unit 3 Sensory systems (weeks 5-7). Here, you will learn the overall organization and function of the sensory systems that contribute to our sense of self relative to the world around us: somatic sensory systems, proprioception, vision, audition, and balance senses. - Unit 4 Motor systems (weeks 8-9). In this unit, we will examine the organization and function of the brain and spinal mechanisms that govern bodily movement. - Unit 5 Brain Development (week 10). Next, we turn our attention to the neurobiological mechanisms for building the nervous system in embryonic development and in early postnatal life; we will also consider how the brain changes across the lifespan. - Unit 6 Cognition (weeks 11-12). The course concludes with a survey of the association systems of the cerebral hemispheres, with an emphasis on cortical networks that integrate perception, memory and emotion in organizing behavior and planning for the future; we will also consider brain systems for maintaining homeostasis and regulating brain state.
Proliferation and Migration, part 1
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Medical Neuroscience
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The Changing Brain: The Brain Across the Lifespan
This module represents another turning point in Medical Neuroscience. Now that we have surveyed human neuroanatomy and our sensory and motor systems, we are ready to take a step back and consider how this magnificent central nervous system came to be the way that it is. We will also learn how the brain re-wires itself across the lifespan as genetic specification, experience-dependent plasticity and self-organization continue to interact, re-shaping the structure and function of neural circuits throughout the central nervous system.
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Leonard E. White, Ph.D.Associate Professor
Department of Neurology, Department of Neurobiology, Duke University School of Medicine; Department of Psychology & Neuroscience, Trinity College of Arts & Sciences; Director of Education, Duke Institute for Brain Sciences; Duke University
Well, just to look at the big picture now of inductive signalling, and this is a
slide from the book that gives you way more detail than I care for you to know
in this course, but it does represent a paradigm that I want you to appreciate.
And that paradigm is what we might call a transcriptional code.
Which reflects the coordinated expression of inductive signals that are coordinated
both in location, but also in developmental time.
And this interaction of inductive signalling is what gives rise to regional
identity within the developing nervous system.
It helps to differentiate one location in the brain stem or spinal cord from
another. It also establishes the dorsal ventral
access of the developing neural tube, which is critical for the development of
sensory neurons. As well as columns of cells that give
rise to our motor output from the brain stem and the spinal cord.
So, these inductive signals really provide for the establishment of the
identity of distinct populations of neurons that are necessary for the
expression of mature function in the human brain and spinal cord.
Now, a similar transcriptional code is responsible for the formation of regions
that go on to form our forebrain, our telencephalon and our .diencephalon.
We know quite a bit less about how this works in the forebrain than in the
hindbrain and the spinal cord, but we're beginning to understand some of the
inductive signals that are responsible for forming the cerebral cortex, the
basal ganglia, other deep forebrain structures, as well as the derivatives of
the diencephalon, including the optic cup and the otic placode, which goes on to
form the structures that are necessary for vestibular function and then,
auditory function. Well, once regional identity has been
established along the length of the developing neural tube, the next major
challenge is proliferation. Making the cells that are necessary to
properly populate the grey matter structures of the developing brain and
spinal cord. And proliferation is just mind-boggling
in the developing nervous system. We know that in the adult brain there are
about 100 billion neurons and if that number doesn't stagger the mind, consider
that there are at least that many, and probably several fold greater than that
number, glial cells in the human central nervous system.
So just an incredible number of cells are present in the brain and the spinal cord.
And in order to produce so many cells, the rate of proliferation is just
staggering. During the peak of the production of
cells in the developing nervous system, scientists have estimated that perhaps as
many as 250,000 cells are produced every minute in the developing embryo.
Another amazing aspect of the proliferation of brain cells, in early
development, is that the production of neurons is restricted in time to a very
narrow period. Nearly all the neurons that we have in
our central nervous system right now were born in the second trimester of
pregnancy. Now there are some brain structures, like
the cerebellum, that has just the enormous number of cells, and I'm
referring to the granule cell population of the cerebellum.
And it takes a considerable longer period of time to populate this cerebellum, so
at least a year, perhaps as long as two years, but with the exception of the
cerebellum, virtually all of the cells that we have in our brain and spinal cord
were born in that second trimester of pregnancy.
Now some of you may know that there is adult neurogenesis, that is, even right
now there are new neurons being born, but, as we'll come to in a few tutorials,
the genesis of those new neurons is restricted to the hippocampus, at least
in our brain and it is perhaps very important that this phenomenon occurs, it
may contribute to learning and memory and other aspects of maintaining our mental
and physical health, but it is a restricted population of cells that grow
into that one region of the brain. And, as far as we know now, the impact of
the stem cells that may reside in the human brain, seems to be limited.
Both in terms of, normal physiological function and the response of the brain to
injury. So, I think there are fairly profound
implications for this restriction of neurogenesis in the formation of the
nervous system. The neurons that we have right now, are
the ones that were born in that second trimester of pregnancy.
So I would encourage you to think about that.
And wonder, well, what are the implications for learning and memory?
What are the implications for rehabilitation following injury, if
that's, if that's the case. Maybe that's something that we can kick
over to the discussion board. And, see if that might inspire some
interesting dialogue. Well, let's talk a little bit about how
this proliferation of brain cells occurs, and then we can go on to talk about how
brain cells are differentiated into neuronal or glial fates.
Brain cells, like most other cells in the body, go through the usual stages of
growth. And the synthesis of new DNA, setting the
stage for the division of the cell into daughter cells, and that division occurs
via a process that we call mitosis. I certainly am assuming that you are
broadly familiar with cell division from your prior studies of cell and molecular
biology so I won't go into the details of how mitosis occurs.
Rather I'd like to talk about how mitosis happens in the walls of the neural tube
that allows for the production of the cells that come to populate specific gray
matter structures that we recognize in the human brain such as the cerebral
cortex or the basal ganglia. Well, proliferation occurs among a
population of precursor cells in the walls of the neural tube.
These precursor cells have a recognizable cell body containing the nucleus, and all
the other organelles that are common to the cells of our body.
And that cell body, then, grows a process that makes contact with the inner and the
outer surface of this wall of the developing neural tube.
The outer surface will, will become the piall surface surface of the brain, and
the inner surface is, of course, the inner surface of the neural tube, that
goes on to differentiate into the ependymal lining of the ventricles in the
human brain. Now, along this path between the pial
surface and the ventricle surface this cell body becomes multal.
That is, it migrates in the up and down directions, towards the pia, and then
back towards the lumen of the ventricle. So, as this cell body begins to
translocate up towards the pial surface, the cell now enters the synthesis stage,
where DNA is being replicated. And then, as DNA is replicated, the cell
body then migrates back down towards the luminal surface of this developing neural
tube as the cell gets ready for division. And it's near the ventricular surface
then of this neural tube that mitosis occurs.
And mitosis can happen in a symmetrical way.
It can produce two precursor cells that can go through this, this dance of
migrating to the pial surface and back to the luminal surface again, and undergo
subsequent cycles of mitosis producing more daughter cells, or there can be
what's called asymmetrical division. An asymmetrical division produces two
different kinds of cells. One cell remains a progenitor cell, which
can go on to subsequent stages of mitosis.
Although it's mitotic potential now is somewhat limited.
The other daughter cell becomes what we call a neuroblast and this is now a
post-mitotic cell that can go on to differentiate into neurons or glial
cells. Now once this neuroblast has been
produced through this process of asymmetrical mitosis, for many of these
cells, they migrate away from the ventricular region of the wall of the
neural tube to a more peripheral destination.
And that migration is important for forming a structure like the cerebral
cortex. So now we're looking a little bit further
along in development. And now the wall of the neural tube is
beginning to become a bit more complex. And if we look at this wall of neural
tube in some detail, we can recognize the ventricular zone, where mitosis is
happening, but increasingly, we begin to develop a separation between the pial
surface and the luminal surface and the wall of the neural tube.
And we begin to populate a structure that now acquires the properties of gray
matter. And this structure, we call the cortical
plate. The cortical plate is the first formation
of the cerebral cortex. So, the challenge here is to get these
neuroblasts that are formed here in the ventricular surface up to the cortical
plate. And this requires a process of migration.
So, the cells must become motile, and they must find their way to this outward
cortical plate. And the way this happens is these
neuroblasts will migrate along a radial fiber that is formed by a presumptive
glial cell, we call this the radial glial cell.
So these are essentially precursor cells now that continue to maintain their
contact between the pial surface and the luminal surface of the developing neural
tube and this long extended process becomes a pathway for the migration of
the neuroblast. So, over here to the right, we have a
dipiction of one of these neuroblast migrating along this radial glial fiber
and these cells will translocate, they will shimmy along this fiber on their way
towards the cortical plate. So there are a variety of factors that
guide this migration. And, along the way, these neuroblasts
begin to further differentiate and acquire a specific identity that will
allow them to be differentiated into a neuron or a glia or a particular sub type
of one of those broad categories of brain cells.
So, as these neuroblasts migrate from the ventricular zone up to the cortical
plate, they do so in a particular pattern.
the cortex is essentially built in an inside out fashion and here are some data
from what's called birth dating studies that have been done to track the final
mitosis of a precursor cell and its ultimate position within the developing
cortical plate. Well, there's a technical means by which
this can be done. It's described in a box in chapter 22, if
you're interested in how this happens. But essentially, what we can do is, we
can label precursor cells at a particular point in development, and simply ask what
has become of the post mitotic neuroblasts that were derived from that
population of precursor cells that were marked at a particular time of
development. And what this approach has taught us is
that the cortex does indeed develop in an inside out fashion.
The cells that are born in, let's say, the late first trimester of pregnancy
come to populate the inner and the outer margins of the cortical plate.
And thereafter, as we progress through the second trimester of pregnancy, the
cells that are born early in that second trimester come to reside in the lower
portion of the cortical plate, in the region that ultimately differentiates
into cortical layer six, the inner layer of the cortex that sits just on top of
the white matter. And as neurogenesis progresses through
that second trimester of pregnancy, extending at least in some cortical
regions into the third trimester, we see this progressive population of the
cortical plate from the inner layers to the outer layers such that the last cells
to take up their residence in the developing cortical plate are those that
reside in what would become cortical layers two and three.
So these neurons that come to reside in the outer part of the cortex have to
migrate through these cells that have already established residence in the
deeper layers of the cortex. And as these cells migrate through these
deeper layers of the cortex, there is yet additional opportunity for inductive
signalling to influence the fate of these later born and more superficial residing
cells in the developing cortex. So this is the pattern by which a cortex
is constructed. An inside out pattern involving the
precise regulation of neurogenesis and the migration of neuroblast.
So, obviously there's a lot of specification that's going on here.
Cells are born at a particular time. They are provided the signals that are
essential for migration and for getting off that radial glial fiber at the
appropriate location such that the cortex is progressively built out in this inside
out pattern. Now unfortunately, we know that some of
the signals that are responsible are subject to genetic mutation.
Perhaps they can be influenced by environmental toxins or dietary factors.
And there are some known phenotypes where this inside-out pattern is destructive.
In fact, the process of neuronal migration and the proper establishment of
this inside-out pattern seems to be essential for establishing the identity
of the cells that take up residence in these various layers of the cortex.
And their location, as you may recall, has much to do with determining the
connections of the neurons that are ending up in one cortical layer or
another. So if this process of migration and
patterning of the cortex is disrupted, it's very likely that also the
connections of those cells will likewise be disrupted.
And we now know that there are a number of congenital malformations of the
cerebral cortex that reflect errors in the migration of these neuroblasts.
We think that perhaps even subtle errors in the migration of these neurons might
be responsible for some forms of mental retardation and learning disability.
Although there's much more work that needs to be done to truly understand
what's going on at the level, at the level of cortical development that can be
related to the broad spectrum of learning disabilities that we confront in society.
We'll say more about that topic as the story of cortical maturation continues in
subsequent tutorials.
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