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.
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Neural Signaling: Electrical Excitability and Signal Propagation
We now turn our attention from the tangible (human neuroanatomy) to the physiological as we explore the means by which neurons generate, propagate and communicate electrical signals. After exploring those structures in the human brain that are visible to the unaided eye, we must now sharpen our focus and zoom-in, as it were, to the unitary level of organization and function in the central nervous system: to the level of individual neurons and their component parts that are crucial for neural signaling.
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
Now, the delayed outward current behaves differently.
It continues to grow monotonically with increasing membrane potential.
Now, these observations together again provide evidence that this transient
inward current reverses near 50 millivolts, while the delayed outward
current increases steadily. Now, knowing something about the ions
that are present in seawater, and having some sense of what the ionic
contributions might be to the cytoplasm within axons, knowing something about
Nernst equation. And then, having the ability to
manipulate some of these empirical parameters in this experiment, allowed
Hodgkin and Huxley to identify what are, in fact, the ions that are caring these
two kinds of currents. What they concluded is that the early
current is carried by sodium. Now, the Nernst equilibrium for sodium
happens to be very close to plus 52 millivolts in their experimental
preparation. That is highly circumstantial evidence
supporting this conclusion that the early current is carried by sodium.
One way to test that hypothesis would be to change the solution that is bathing
the neuron. And if you substitute the solution with
one that removes all sodium, the prediction would be that the inward
current ought to reverse to become an outward current.
Because even though the normal physiological concentrations of sodium
are much greater outside than they are compared to inside, if you artificially
remove all sodium from outside the cell, there will be a concentration gradient
favoring the efflux or the outward flux of sodium.
And that appears to be what is recorded in this experiment.
Then, returning back to normal physiological conditions, similar to what
we find in sea water, the inward current is, once again, restored.
This conclusion is further supported by experiments using a toxin found in
nature. A toxin called tetrodo-toxin found in
the, a puffer fish. And when that toxin is applied to this
axon, what we find is that the transient inward current is blocked.
All we're left with is a delayed outward current with the application of
tetrodo-toxin. So, that result provides additional
empirical evidence supporting the conclusion that the early current is
carried by sodium. Now, additional experiments were done
using a tetraethyl-ammonium ion, which is now known to block potassium channels.
And when that ion channel blocker is applied to this preparation, what we find
is that the delayed outward current is removed and all that we find is the
transient inward current. So, this is very good evidence supporting
the conclusion that the late current is indeed carried by potassium ions.
Okay. Well I think we're ready to move on in
our consideration of these data. And I want to introduce an additional
concept that I think helps us come a little bit closer to the underlying
biological mechanisms that explain the ionic basis of the action potential.
And this concept that I want us to think about is conductance.
Now, we're familiar with Ohm's law from our study of Physics, right?
So, Ohm's law is V equals IR or voltage equals current times resistance.
Well, this concept of conductance, well, has more of a formal expression.
for our purposes, we can represent conductance by the lower case letter g
and simply state that it's comparable to the inverse of resistance.
So, it's possible then to rewrite Ohm's law in terms of current.
And what we can state, then, is that measured current is proportional to the
conductance for that permeant ion times the voltage.
Now, this voltage term is interesting. This voltage term provides the driving
force for the current that we can record that is passing through a neural
membrane. But in order for that current to actually
flow, not only must there be a driving force, but there also has to be some
means by which that ion can pass through the membrane, which is to say, there
needs to be conductance. So, I want you to appreciate using this
version of Ohm's Law that current flow really requires two kinds of functions.
There needs to be conductance greater than zero and there needs to be some
voltage that creates a driving force term.
And so, rather than saying that the voltage needs to be greater than, than 0,
what we need to express is that the voltage must be greater or different from
the Nernst equilibrium potential for the permeant ion.
Okay. So, this allows us now to return to our
experimental situation where we changed membrane potential and recorded current.
But now, we get to introduce this version of Ohm's law that helps us understand the
movement of ions in terms of the conductance of the membrane for the
permeant ion. Again, what we have here is current,
which can be measured experimentally. we know something about the membrane
potential of the neuron. And, given the concentration gradient of
the permeant ion, we know it's Nernst equilibrium potential.
So, the driving force term then becomes the difference between the membrane
potential at any point in time and the Nernst equilibrium potential for the
permeant ion. So, what would happen then if the
membrane potential is exactly the Nernst equilibrium potential for the permeant
ion? Under that situation, the driving force
is equal to 0 and no net current is going to flow.
This is one way to establish electrochemical equilibrium for a
permeant ion. That is, it's possible with the
patchplant method to set the membrane potential exactly to the Nernst
equilibrium potential for the ion in question.
Well, this formulation should make it obvious that there is another way in
which to have no net current flow for an ion, and that is when conductance is
equal to 0. That is, when there's no means by which
an ion can cross a membrane, there may be a driving force.
But if there's no conductance, then the measured flow of that current is going to
be 0. Okay, well, these are some theoretical
ways of considering the experimental results obtained by Hodgkin and Huxley.
And what's shown now in the lower part of figure 3.3 are the same data, except now
the measured ionic current is expressed in terms of the conductance that is
associated with the transient current and the delayed outward current.
now having confidence that, that inward transit current is carried by sodium and
the delayed current is carried by potassium.
So, what we can now do is express these current fluxes in terms of conductances
for sodium and potassium. So, let's look at these one at a time.
When we look at the conductance change for sodium with depolarization, what we
see is a very sharp and steep rise in sodium conductance that happens with
increasing depolarization. So, it should be obvious then that the
sodium conductance is voltage-dependent. But look what's going on here.
Even with a sustained depolarization, this conductance that quickly rises well
above 0, falls back towards 0, even though we continue to clamp the axon
membrane to some value as indicated here in the figure.
So, this tells us that this conductance is not only voltage-dependent, but it's
also time-dependent. Actually, the same conclusions can be
made with respect of the potassium conductance, but in a different way.
What we see is with increasing depolarization, there is a growth to this
potassium conductance. So, like the sodium conductance, [SOUND]
there's evidence for voltage-dependency. But notice, the growth is gradual and the
onset of this conductance is relatively slow compared to the onset of the sodium
conductance. So, there is an element of
time-dependency that we see for the potassium conductance.
Now, that conductance does not fall back down sharply the way we saw for the
sodium conductance, rather, the time-dependency is in the relatively
gradual onset of this rise in potassium conductance that we see.
So, nevertheless, both conductance are time-dependent.
But the time-dependency seems to suggest that there may be different molecular
mechanisms that mediate those time dependencies.
Okay. Let's return now to the sodium
conductance and make an additional point about this rapid fall in sodium
conductance that we see after the rapid rise.
So, we actually have a term for this, we call this inactivation.
Now, as we'll see in the next tutorial, inactivation is not exactly the same
mechanism as simply closing an ion channel.
so, we're going to want to understand that point in the next tutorial.
But for now, I'll just highlight the fact that the sodium conductance inactivates.
[SOUND] And what we mean by that is this rapid fall and conductance that follows
the rapid rise. Now notice, the potassium conductance
does not inactivate, so there's no inactivation [SOUND] of the potassium
conductance. Now, there are certain types of potassium
conductance that can be found in certain neurons that do, in fact, inactivate much
like the sodium conductance. But not this conductance, not in this
axonal membrane from which these experiments are derived.
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Leonard E. White, Ph.D.Associate Professor
