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.
Inductive Signaling In CNS Formation
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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.
Rencontrer les enseignants
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, now that you've been able to refresh your understanding of the anatomy
of the adult form of the human brain in relation to the changes that took place
in the neural tube, that gave rise to this fantastic form, what I would like to
do is to begin to talk about some of the genetic and molecular mechanisms that are
responsible for establishing regional identity along that developing neural
tube that ultimately leads to the formation of the human brain.
Well this story, really took off as biologists began to explore the genetic
basis of development in invertebrate systems and of course one of our favorite
invertebrate model systems in biology is the fruit fly, drosophila, and what was
discovered is that there are a set of genes that help to define.
The segments of the developing drosophila larva.
So here is a representation of the drosophila larva.
And what we appreciate of course, is that this animal has a segmented body plan.
So what was discovered several decades ago is that the segmentation of this
developing larva reflects the expression of particular genes that establish
regional identity. Such as this first thoracic segment of
the larvae, which goes on to form what we call the prothorax and the drosophila.
and it's from that prothorax that particular.
body parts emerge, such as this first limb that emerges from the transformed
larva into the adult form. Well, much molecular and genetic biology
has gone on over the decades, and we've come to recognize that this segmentation
of the developing larvae into an adult form reflects the expression of what we
call, in drosophila, Hox genes, and their homologues in mammalians, including
humans are called homeotic genes. So, in the human genome, we now know that
there are four clusters. Of these Hox genes or these homeotic
genes. Sometimes we call them Homeobox genes.
And these clusters are responsible, we think, for beginning to establish some
regional identity in the developing nervous system.
There is an anterior to posterior pattern of expression of these clusters.
Of Homeotic genes that help to establish, for example, the various segments of the
human spinal chord. And the major divisions of the brain
stem. Well, why should this be important?
Why should you be motivated to learn something about these homeotic genes?
Well, I've already challenged you to consider in some detail, the anatomy of
the differential regions of the human brain stem for one very good reason, to
understand the location of the cranial nerves in relation to divisions of the
brain. So, hopefully you recognize the, relation
of the trigeminal nerve to the pons and at the junction of the pons and the
medulla we have an abducens nerve which is not present in this particular
specimen, but we see very nicely here our cranial nerve seven.
The facial nerve. And certainly a very beautiful
vestibulocochlear nerve present, cranial nerve eight.
And even just, you can see I think here, just a few nerve roots of cranial nerve
12, between the medullary pyramids and the olive, which is present out here
laterally. Well, the relationship of these cranial
nerves to particular regions of the developing brain stem seems to reflect
the specific expression of homeotic genes that help to identify regional identity
along the length of the developing neural tube.
This is especially important. For the specification of position within
the developing brain stem. we see the expression of particular motor
nuclei of the brain stem, for example, that seem to be derived from particular
regions of the brain stem that express a set of these homeotic genes.
So this is an example of genetic specification determining regional
identity and there are probably inductive signals at work here that establish this
identity. And one of the many outcomes of this kind
of inductive signaling is the specification of the identity of neurons.
That go on to form critical structures that are important for form and function
in the human nervous system, including these cranial nerves.
So, if you've wondered why are the nerves found exactly where they are in the human
brain, part of the answer is going to have to do with the differential
expression. Of homeotic genes at particular points in
development and at particular locations along the length of the developing neural
tube, especially in that region that goes on to form the brain stem.
Well, next I'd like to turn our attention to.
This matter of inductive signalling and give you a few examples, not to overwhelm
you with molecular detail but rather to give you a feel for how inductive
signalling works and how these signals that are secreted out into the
extra-cellular spaces in the developing embryo.
Can have such a formative impact on the fate of cells that are in the process of
developing within the walls of the neural tube.
Well, as I mentioned, inductive signaling really begins in earnest in nur relation
as the neural tube begins to form. And signals are expressed by this
notochord that begin to influence the differentiation of these special regions
in the neural tube that establish a dorsal ventral access.
There is a floor plate that begins to give rise to it's own signals.
That will establish a ventral identity in this region of the developing neural
tube. And I think you know enough now about the
spinal cord to connect the dots here and realize that ventral identity is going to
give rise to motor circuits and alpha motor neurons that will grow out and.
Connect the central nervous system to effector systems, namely our stride and
muscles. Meanwhile, this roof plate will give rise
to inductive signals that establish a dorsal identity in the developing walls
of the neural tube. And dorsal, I think is you reflect on
your understanding of the spinal cord, implies the development of somatic
sensory neurons that are receiving incoming information about the
experiences of our peripheral tissues. And integrating them within the central
nervous system, giving rise to. Local circuit connections, as well as
long distant pathways that convey somatic sensory signals to more rostral regions
of the developing brain. So, dorsal and ventral become really key
regions within the developing neural tube that have an influence on the ultimate
fate of the cells that are developing in those regions.
So, I'd like to give you some specific examples of these inductive signals so
you have a big of a feel for really what's going on here.
So one of the best understood inductive signals is called retinoic acid.
So retinoic acid is a small lipophilic molecule, metabolized from Vitamin A.
It's a very important inductive signal and it's one of the principle substances
that explains the importance of Vitamin A for early brain development.
So, Retinoic Acid is synthesized and released as a [UNKNOWN] molecule.
It can readily translocate through cellular membranes.
And it can bind to a receptor within the cell, and that receptor becomes a
transcription factor that translocates to the nucleus, and it can interact with
other binding proteins and turn on particular genes.
And so that's what we see here. We see retinoic acid interacting with its
receptors and other complexes that can modulate gene expression.
Now retinoic acid provides one of those examples where the life experience can
have an impact on the developing brain. Insufficient Vitamin A in the diet of the
mother can have an impact on the capacity to produce this important inductive
signal and there can be deleterious consequences for the formation of the
early nervous system. There is an additional problem that can
be encountered with respect to retinoic acid signaling.
And that is an excess of vitamin A. And there are a variety of dietary
supplements and even topical agents that can be purchased for other reasons that
include Vitamin A or Retinoic Acid, and excess Retinoic Acid in the developing
embryo likewise can be extremely harmful. In fact Retinoic Acid can become what's
called a teratogen which is a exogenous substance that can induce malformations
in the developing embryo. If you'd like to learn a little bit more
about this particular topic, I would refer you to box 22c found in our
textbook, which gets you a little bit more of the back story regarding how
Retinoic Acid signaling shapes the developing brain.
Well, let's consider some other kinds of inductive signals.
Most of our conductive signals are actually not, steroid hormones.
They are peptide hormones. So, these are substances that are
secreted and interact with surface bound receptors.
And one of our peptide hormones that I'd like to talk just a little bit about is
called bone morphogenetic protein or bmp for short.
And the way bmp works is that it interacts with a surface receptor here we
see, bmp being secreted. by one kind of cell and it interacts with
this receptor. And the receptor is what we call a serine
kinase. So this means that it phosphorylates a
serine residue in target proteins. And this serine kinase phosphorylates a
transcriptional regulator. Called s, m, a, d, or smad for short.
This is an acronym you don't need to worry about, its name, but I do want you
to understand something about how this system works.
So, he activated smad then associates with additional helper proteins and this
then trans-locates to the nucleus where it acts as a transcription regulator.
Now, B M P signalling is especially important in mesodermal tissue.
As the name implies Bone Morphogenetic Protein, bmp signaling can induce the
development of bone cells. Now, in ectoderm, bmp signalling can
induce the formation of epidermis or skin, unless bmp signal is controlled.
And this is where these additional factors that are illustrated here come
in. There are factors called noggin and
chordin; they have somewhat fanciful names.
That can antagonize the interaction of bmp with it's receptor.
When noggin and chordin antagonize the bmp signaling pathway preventing BMP from
interacting with it's surface bound receptor, that's ectoderm will be
diverted from an epidermal fate. to a neural fade, with noggin and
chordin, this tissue will differentiate into what we call the neuroectoderm, or
the neural plate. Now, I think that this is a really cool
and fascinating thought which I've highlighted for you in your tutorial
notes, and that is That what these molecules noggin and chordin really do is
they rescue this ectoderm from becoming skin.
They induce the differentiation of this neural plate and, subsequently the
formation of the entire central nervous system.
So from that point of view I think we can all thank our noggin and chordin for
giving us a brain and a spinal cord. One last inductive signal I'd like to
just talk through is one that has perhaps the most memorable name of all especially
those of you that have some history in video gaming.
This inductive signal is called SHH, or Sonic Hedgehog, and Sonic Hedgehog is a
protein hormone that interacts with receptors that are bound to the surface,
and its receptor is a protein called patched that interacts with a protein
called smoothened, and these interactions will go on to activate a series of
transcription factors that were originally identified in brain tumors or
gliomas, and when. Sonic Hedgehog interacts with patched in
the presence of smoothed, what we find is a switch in the transcription factors
that are regulated within the cell. And, specifically, this Gli1.
becomes induced, and it binds to DNA, and modulates gene expression.
This Sonic Hedgehog mediated signaling pathway is critical for the proper
closure of the neural tube.
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