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.
Spike-Timing Dependent synaptic Plasticity
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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
Welcome to the second of the three tutorials that I have for you about
synaptic plasticity. In this tutorial, we're going to talk
about spike timing-dependent plasticity. So again our concern is for three very
important core concepts in the field of Neuroscience.
We continue to talk about the communication among neurons, using
electrical and chemical signals. And how life experiences can change the
structure and function of the nervous system.
And as we learn more about these fundamental properties.
We are going to learn how better to promote healthy living and the treatment
of disease. So again, this is a very exciting field
in modern Neuroscience. And the future couldn't be brighter in
terms of anticipating how discovery in the field of Neuroscience is going to
improve the human condition. Our learning objectives are again to
characterize general cellular mechanisms for synapatic change.
And then I want you to be able to discuss the importance of the timing of the
postsynaptic response relative to the presynaptic activity.
For the mechanism of synaptic plasticity that we observe in the postsynaptic cell.
So those are our learning objectives. And to get started, let's review, again,
the general cellular mechanisms that lead to synaptic plasticity.
Well, we went over this in the previous tutorial and perhaps it bears repetition.
synaptic plasticity begins when neural activity triggers the activation of
postsynaptic second messenger systems. The trigger in that postsynaptic cell is
typically an alteration in the level of intracellular calcium.
The level of intracellular calcium is critical, because calcium-dependent
second messenger systems are then activated.
And those systems can then activate either protein kinases, which
phosphorylate target proteins. Or protein phosphatases, which
dephosophorylate target proteins. And it's the alteration in protein
phosphorylation that either turns on or turns off target proteins.
And together, these events mediate the early stages of long-term synaptic
plasticity. So these are mechanisms that are
operating upon cellular molecular machinery already present within the
postsynaptic cell. Long-term synaptic change, however,
requires alterations in gene transcription.
So this is the general scenario by which plasticity plays out typically in a
calcium dependent manner. And the key difference between one
valance of plasticity, if you will. Or another, is the level of intracellular
calcium that's triggered by the synaptic activity.
Well, what I want to tell you about today in this tutorial is, something called
spike timing-dependent plasticity. And I want to make clear, I'm not talking
about a totally different form of plasticity.
Than what we've already discussed in terms of long-term potentiation and
long-term depression. Rather, I want to help you understand
through this spike timing-dependent framework.
How plasticity plays out in ongoing patterns of activity in the brain.
Spike timing-dependent plasticity provides for us a framework for
understanding plasticity in the brain one postsynaptic spike at a time.
And here's what I mean by that. Real synapses seldom, if ever, experience
brief trains of high frequency stimulation of the sort.
That were used in the hippocampus slice preparations, in order to demonstrate
long-term potentiation. So one might reasonably ask.
How, then, does plasticity work in real circuits?
if they don't experience the kind of stimuli that typically were used at least
in the classical studies of long-term potentiation.
Well, here's the spike timing-dependent plasticity framework.
again, it allows us to understand these principles of plasticity.
One spike at a time without necessarily depending upon a special train of stimuli
in order to induce a synaptic change. So, consider a synapse where we've got a
presynaptic input to a postsynaptic neuron.
And in our experiements that I'll be talking about here.
It's possible to stimulate the presynaptic axon.
And induce a action potential at that presynaptic terminal, at some period of
time. Either before or after an action
potential is recorded in the postsynaptic neuron.
Now if this is a mature, strong synapse. You might anticipate that activity in the
presynaptic terminal will lead to the generation of an action potential in the
post synaptic cell. And indeed it's possible to find such
synapses for which that behavior is observed.
And that's what we find in this illustration here in figure 8.18 from
your textbook. So, there is an action potential in the
presynaptic cell. And about 20 milliseconds later, there is
an action potential in the postsynaptic cell.
So we call this presynaptic activity before postsynaptic activity.
This is what we might expect if our presynaptic cell, let's call that neuron
A is firing an action potential. And that leads to the activation of our
second cell, we call call that neuron B. So for such a synaptic connection, it's
possible to look over time. What is the amplitude of the postsynaptic
potential or the postsynaptic current. following some, structured pairing of
activity between the pre and the postsynaptic element.
And so that's what's being shown here in this recording we have excitatory
postsynaptic current amplitude on the y axis.
And time on the x axis relative to some structured stimulation between the pre
and the postsynaptic element. And what we find is that when we provide
that stimulus. Where the presynaptic input happens
before the postsynaptic input. Then there is an elevation of the
excitatory postsynaptic current. So, the amplitude is increased by about
40%. And so this is evidence of long-term
potentiation in this pre-before postsynaptic regime.
Now, since we can control the activity with our microelectrodes.
It's possible to stimulate the presynaptic terminal.
at a time that actually comes following the generation of a postsynaptic action
potential. Now, I'll just ask you to remember that
our typical neurons that we have in structures like the cerebral cortex
recieve inputs from many hundreds even thousands of different synaptic
connections. Different exonal inputs converging upon
the dendrex at the very same cell. So that cell might fire an action
potential in response to activity. And one of these many other hundreds or
even thousands of inputs. So, we're studying one particular
synaptic connection. And we're varying the timing at which
that input is activated relative to the firing of a postsynaptic action
potential. So if we stimulate such that the
postsynaptic action potential actually happens before the presynaptic action
potential. We might find a recording that looks like
this. So, the large action potential represents
the postsynaptic spike. And then some period of time following
it, maybe 30 milliseconds or so later. The presynaptic input is stimulated.
And we see some post synaptic potential that's recorded.
But that post synaptic potential importantly in this regime follows the
triggereing of the action potential. And under that situtation where post
synaptic activity happens before pre synatptic activity.
Notice that there, now is the development of a weakening.
And the amplitude of the excitatory post-synaptic current.
This is long-term depression. This is what happens, basically when the
postsynaptic neuron is being influenced to fire an action potential by some other
input. Other than the one that we're stimulating
in this experiment. When experiments such as these can be
done over and over again, varying the interval between presynaptic activity and
postsynaptic activity. It's possible to generate a function that
now accounts for spike time-independent plasticity.
And what we see is that in the pre before post regime, that is, when a pre-synaptic
input is in a position to fire the postsynaptic cell.
There may be a marked degree of potentiation.
So this then is long-term potentiation. That can be recorded if the interval
between the pre synaptic firing and post synaptic firing is less than about 20
miliseconds. Now 20 milliseconds it's, it's kind of
magical interval. if you follow me here, that's an interval
that's suggestive of a milo synaptic connection.
Where the input in question, the one that we can control with the micro-electrode.
Is effective in triggering the action potential in the postsynaptic cell.
We might think of this as their as providing some coordination of activity.
If you will, between the pre and the postsynaptic element.
Where the presynaptic input is reliably leading to the activation of that
postsynaptic cell. So pre before post leads to long-term
potentiation. On the other hand, again, we're calling
that postsynaptic neuron is going to be receiving hundreds of thousands of other
inputs. It may fire an action potential in
response to some other input than the one that we have control of with our
microelectrode. Well, should that happen before the
stimulus is applied to the input in question.
We might have long-term depression in this post before pre-regime.
So this now is long-term depression where the excitatory postsynaptic current is
actually diminished. When the firing of the postsynaptic cell
precedes the firing of the input in question.
So we might imagine that this post before pre is a picture of incoordination
between the pre and postsynaptic elements in question.
Well, here, in this part of the country, especially as winter is turning into
spring. one sport that is popular in my own
family, anyway, is baseball. And baseball involves a pitcher throwing
a ball at a batter, that has a, wooden or a metal bat.
And the batter has to time the swing just right in order to hit that baseball.
Well, if the batter begins to swing the bat just at the right moment in time.
Then he or she might strike the ball and might hit a homerun.
That's a good thing for the batter. We might consider that to be a mediphore
for long-term potentiation. If the swing of the bat occurs at just
the right time. As the ball is entering the hitting zone.
Then the batter begins to pass the bat through the hitting zone and the two make
contact and well. That's a good thing for the batter.
So we'll call that long-term potentiation.
Well, there's a particular kind of pitch in the sport of baseball that's intended
to deceive the batter. The batter sees the pitcher release the
ball. And the batter anticipates that the ball
is going at a faster rate than it actually is.
This is called a changeup pitch, meaning a change in the speed of the ball.
Well, an effective changeup will result in the batter swinging too early.
That is, the bat will pass through the hitting zone before the baseball arrives.
I like to think of that, as post before pre.
The bat passes through the hitting zone too soon before the opportunity to hit
the ball arrives. Well that's not a good thing for the
batter. We might call that long-term depression.
Well, I was actually invited to think about this metaphor by a student I had a
few years ago. Who thought about this spike
timing-dependent plasticity function and said, oh, so long-term depression is a
near miss. And I thought, exactly, it's a near miss.
Like, swinging through a changeup. It's a near miss.
The batter swings the bat, but prematurely, before the arrival of the
baseball. The postsynaptic activity happens just
before the presynaptic activity. That's actually quite bad for that
synaptic connection. That leads to the depression of that
connection. Whereas if the batter never swung the
bat, if it stayed on his or her shoulder, there'd be no strike.
Well, I think that's an important lesson. In order for the synaptic connection to
be depressed, it actually has to be used. But it has to be used poorly.
That is to say, there has to be some incoordination at that synapse.
Where the postsynaptic neuron fires in response to some other input.
Not the one in question. But it needs to be a near miss.
That postsynaptic neuron needs to fire before, but just before the presynaptic
neuron. Now, I want you to notice something about
the shape of this function. Notice that the shape of the long-term
potentiation phase,[SOUND], is roughly about half the width of the shape of the
long-term depression function. Well, I think that's kind of interesting.
my background is in developmental neurobiology.
So I like to think about how plasticity works out in the context of development.
And as neural circuits become active, there seems to be a lot of noise and
those activity patterns that develop in the brain.
We might think of that noise as being somewhat unstructured.
And somewhat unshaped by either the brain itself or by it's interactions with the
outside world. Well, if the interval for depression is
twice as large as the interval for potentiation.
Then that suggests that more of that noise is going to fall in the phase of
this function that favors depression. Such that the noise is going to tend to
lead to the depression of those active synaptic connections.
Whereas those synaptic connections that are mediating some structure, where there
is preactivty, presynaptic activity leading to postsynaptic activity.
That's coordination. So as signal emerges out of the noise of
the developing brain, there's the potential to focus in on that signal.
Potentiate those synapes that are effectively driving activity in those
circuits. And meanwhile depress the other weaker
inputs that are out of sync, that are not being coordinated, not being structured.
So this may be one mechanism by which the brain imposes a temporal filter on i'ts
own activity patterns. As a way of selecting those that are
leading to an increase in the coordination of firing across synaptic
connections. Well, one way that the brain has of
imposing some structure over it's spatial and temporal patterns of activity is
through interactions with the environment.
And in context of the developing brain, it's intriguing to hypothesize that
sensory experience might be one source of structure.
That favors the potentiation of functional synaptic connections.
Whereas, the noise that otherwise is not being well structured by sensory
experience, might lead to depression. And perhaps the weakening, and maybe even
the loss and the pruning away of synaptic connections that are, that are not
functional. Well, this brings us to the close of this
tutorial. The third and final tutorial in this
series will put all of this together in a very powerful framework.
That has been with us through many decades now and continues to inspire our
understanding of synaptic plasticity. So we'll talk about Hebb's Postulate in
our next session.
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