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.
Ionotropic Neurotransmitters Receptors, part 2
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Medical Neuroscience
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Neural Signaling: Synaptic Transmission and Synaptic Plasticity
Let’s continue our studies of neural signaling by learning about what happens at synaptic junctions, where the terminal ending of one neuron meets a complementary process of another excitable cell.
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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
So how did you do? Did that make sense?
Did you have to back up, a few minutes in the tutorial and look back at the data
that we just went through? Well, if you did then that's great but if
you, found it a bit confusing then hang with me now.
Let's look at a similar experiment. only now taking it to the level of the
passage of current through a single ion channel.
Okay, so let's see what happens when we focus again on the nicotinic
acetylcholine receptor and the movement of ions through that receptor channel.
So what we're going to do is to consider the flow of current that can be recorded
while this membrane is clamped at different membrane potentials.
So let's being at minus 100 millivolts. So what can be recorded is a strong,
inward current that results in a depolarization of the muscle fiber.
So we're still at the end plate so we're going to call this an EPP for an end
plate potential But it's just the membrane potential of the muscle fiber.
OK, and it's depolarizing relative to rest.
So, why is it depolarizing? What explains the strong, inward current?
Well, sodium ions are going to, pass through this ion channel.
This channel, because of its molecular properties, is permeable to both sodium
and potassium, but at minus 100 millivolts, there's a huge driving force
for sodium but almost no driving force at all for potassium, because 100 millivolts
is very near the Nernst equilibrium potential for potassium.
So, making the inside of the cell that negative is going to draw in the
positively charged sodium ions which are going to want to flow into the cell
anyway because of its concentration gradient.
So if we have, slightly, less, polarization minus 90 millivolts maybe
now we are just. a little bit less polarized than the
neurist equilibrium potential for potassium.
What we'll find is still strong sodium influx, so we still record a net inward
current and significant depolarization significant end-plate potential.
But notice now, that we also might observe a small efflux of potassium.
Much less than the stronger influx of sodium, which is why we're still
recording an inward current, but it's not quite the same magnitude that we say at
minus 100 millivolts. So now let's clamp this membrane at 0
millivolts. And at 0 millivolts what we observe is no
end plate current and with no end plate current we have no en plate potential.
Now that doesn't mean that there's no movement of ions in fact sodium.
Is still being driven into the cell. we are nowhere near the nearest
equillibrium potential for sodium within the cell so sodium is still going to be
drawn in because of the electrical gradient and also because of its
concentration gradient. In a similar fashion but in the opposite
direction potassium is going to flow out of the cell.
Potassium will be repelled by this depolarization of zero millivolts and
it's going to flow down its concentration gradient.
So there are ionic fluxes but the key is is that thre is no net ionic flux.
So the net current is zero. And in essence, at zero millivolts the
influx of sodium ions is exactly counterbalanced by the eflux of potassium
ions. That's why, in fact, there is no end
plate current recorded. Okay, lastly, let's depolarize the cell
to plus 70 millivolts. So, for muscle fiber, +70 millivolts, is
getting very close to the nearest equilibria potential for sodium, given
the concentration of sodium inside and outside of the muscle fiber.
So, at +70 millivolts, the driving force for sodium Is essentially nil because we
are very close to that Nernst equilibrium potential even though the conductance of
the channel is wide open. However, we are far from the Nernst
equilibrium potential for potassium. So there's a huge driving force for
potassium. That's going to allow potassium to rush
out of the cell It's diffusing down its concentration gradient but it's also
being repelled by the positivity that we have imposed upon the inside of this
muscle fiber. So, as a consequence, what we can record
then is an outward current. And that efflux of positive charge leads
to a hyperpolarizing end plate potential. Now, let's return to the brain.
And let's consider, the inotropic receptors that are found at glutamatergic
synapses. Now, as we've already seen, there are at
least three types of glutamate receptors. we'll focus primarily on two of them.
The receptor for AMPA or ampa. And the receptor for NMDA.
When ampa is placed on a typical neuron in the brain, what we see is a very quick
current that flows into the cell. typically leading to an excitatory
postsynaptic potential, so we call this an excitatory postsynaptic current.
So a very sharp very large inward current that happens very rapidly when when AMPAs
are apply, applied to a neuron. If the compound N-methyl-D-aspartate is
applied What we find is also an inward current but it's not as large an
amplitude and it's a little bit slowly developing and it lasts a bit longer than
the very fast, short ampicurrent. So these different profiles reflect the
activation of different types of receptors both of which bind the
andogynous ligent Glutamate. So, let's look in a bit more detail now
at the behavior of one very important ionotropic receptor for glutamate, and
that's the NMDA receptor for glutamate. So, here in the upper right, we see an
illustration of this receptor. It is a receptor that is formed by the
aggregation of typically four subunits. It has a binding site for glutamate, on
some of the subunits, and sites that bind other types of molecules.
I mentioned that glycine Is a co-transporter in the central nervous
system. There's a binding site on these sub-units
for glycine. so, in order for the channel pore to
open, both glutamate and glycine have to interact with their receptors on this
channel complex. But, there are other binding sites as
well. In particular, there is a site deep
within the pore of this channel where magnesium ions can aggregate.
And, this is a problem for the conductance of the channel, because even
if the pore of the channel is opened, by the binding of glutamate with the
co-agonist glycine, current is not going to flow through this channel if magnesium
is present. Magnesium essentially blocks the flow of
current through the channel. However it's possible to get rid of that
magnesium and the way that happens is by depolarising the membrane, so if the
inside of the cell becomes, more positive.
That positivity can expel this magnesium ion out from the pore of the channel.
When that happens, now the cations that can pass freely through the selectivity
filter of the channel are free to do so. And those include sodium and calcium
ions, that can enter the cell, and potassium ions that can leave the cell.
So this is a ion channel that's permeable to cations but not particularly selective
for one kind of cation or another. And importantly The conductance through
this channel is influenced by magnesium ions.
When magnesium is bound, there's no conductance.
When magnesium is expelled, then we see conductance.
This relationship is charted below in the graph that relates the excitatory
post-synaptic current. To the potential of the post synaptic
membrane and what we see is that when there is the presence of the transmitter
glutamate and magnesium ions there is little to no excitatory postsynaptic
current. Record it at hyper-polarizing potentials.
But, as the membrane potential begins to depolarize, when we get into this range
here, now we begin to see some excitatory post-synaptic current passes.
What happens is, the magnesium block is relieved.
And positive cations, sodium and calcium, can enter the cell.
But notice that as we begin to depolarize towards zero millivolts the current
reverses. Now look at the behavior of the
excitatory post-synaptic current if we remove magnesium from the solutions
bathing the cell. In that situation, we have a relatively
linear relationship between current and membrane potential.
Which is what, one might expect, if there were not this blockade effect, due to the
binding of magnesium ions to the inside of the pore of the ion channel.
Now, before we leave our NMDA receptor channels for the present time.
I just want to highlight the fact that the ion channel allows for the permeation
of calcium. Now this may not seem very important at
this juncture of the course, but it is soon to be extremely important.
Because, as we'll see in a couple of tutorials.
Calcium is critical for mediating synaptic plasticity and the influx of
calcium whether we have a rapid significant rise intracellular calcium or
perhaps a slower and less significant rise in intracellular calcium could make
all the difference in the world. Between strengthening a synaptic
connection and weakening that synaptic connection.
And as we now understand the NMDA receptor channel is a key coincidence
detector of post synaptic depolarization in pre-synaptic activity, which is
critically important for understanding how synapses increase or decrease their
synaptic strengths. So we'll come back to the NMDA receptor.
When we talk about synaptic plascisity , we're specifically focusing in on the
important role of calcium.
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