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.
Function of Basal Ganglia Circuitry
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Duke University의 강좌에서
Medical Neuroscience
1231개의 평가
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Movement and Motor Control: Modulation of Movement
Next, we will consider two major brain systems that modulate the output of upper motor neuronal circuits: the basal ganglia and the cerebellum. Take note: the output of these systems is NOT directed at lower motor circuits directly; rather, their output engages the motor thalamus and brainstem upper motor neuronal circuits. Thus, the actions of the basal ganglia and cerebellum are to modulate, rather than command, the activities of upper motor neurons. As you study the lessons in this module, appreciate how the basal ganglia and cerebellum function in a somewhat complementary fashion to modulate the initiation and coordination of movement, respectively.
강사 만나기
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
Okay, in part two of this tutorial what I want us to do is to consider the function
of the circuitry in the basal ganglia. So my learning objectives for you are
that I want you to be able to discuss the role of the basal ganglia in the
initiation and suppression of behavior. That's ultimately what this circuitry is
going to accomplish. I want you to understand the important
principle of disinhibition, which is played out all over the nervous system
but here in the basal ganglia it's especially critical for understanding how
this circuitry works. So I want to be able to explain how this
concept of disinhibition applies to the circuitry and to the functions of the
basal ganglia. And I want you to be able to discuss the
critical role of dopamine in facilitating the function of these basal ganglia
circuits. Because as I hope to impress upon you,
dopamine really makes the basal ganglia function.
It facilitates. The balance of activity that's essential
for the role of the basal ganglia and the modulation of movement.
So let's consider this notion of disinhibition.
So, what is disinhibition? Disinhibition is the inhibition of
inhibition. Did you follow that?
So the implication here is that there are two inhibitory neurons connected to one
another, in series. So I really want you to study this figure
that we have in front of us you can either look at it in your text book or
just freeze frame this video, and make sure you understand conceptually what's
happening. So again, for disinhibition, we need to
have two inhibitory neurons connected up in series, and that's what we have here.
So, so, neuron A is releasing an inhibitory transmitter on neuron B,
neuron B is releasing an inhibitory transmitter on neuron C.
So, these are our two inhibitory neurons. Inhibitory neuron number one, and then
inhibitory neuron number two. That provides us with the basic
ingredients for disinhibition. So, while this figure is largely
conceptual, and highly schematic, it's intended to represent the actual major
cell types that are found in the basal ganglia.
So notice, for example, that the striatal neuron, represented by this neuron A, is
receiving inputs from the cerebral cortex that are driving the activity of the
striatal neuron when these cortical inputs converge in space and time in the
striatum. Now that excitatory drive is going to
lead to the release of inhibitory neurotransmitter on the globus pallidus.
Since the globus pallidus itself is releasing an inhibitory neurotransmitter
on the thalamic neuron, then activity in the striatum is going to shut down the
activity of the globus pallidus. And if we remove the inhibition of the
globus pallidus on the thalamus, well, I hope you'll understand that that means
that the sciatic neuron is going to release neurotransmitter.
And drive activity in the motor cortex that then can lead to the generation of
action potentials down the corticospinal tract.
So, I'll give you just another moment to look at this figure, and consider how
this works. And again, the key feature here is to
recognize that if the functional goal. Is to trigger activity in the motor
cortex. What is necessary, then, is to remove the
inhibition on the thalamic projection to the cortex.
When we remove that inhibition, that releases the motor division of the
thalamus to fire action potentials. And trigger the activation of our
corticospinal pathway. The circuitry of the basal ganglia then,
in the direct pathway in particular, is setup to remove that inhibitory lock that
the internal segment of the globus pallidus has on the thalamus.
So let's look at this now with a little bit of schematic physiology there to, to
guide our understanding. So, imagine now that neuron a in this
striatum is at rest. So there's not a particular plan to move,
a desire to move, an urge to move. The motor cortex is essentially at rest.
So the relevant part of the striatum is going to be silent.
Well, for reasons that I haven't mentioned yet, the activity of the
internal segment of the globus pallidus is quite high.
So there is tonic activity being generated here in this globus pallidus.
That is causing inhibitory neuro transmitters to suppress the firing of
the ventral anterior and ventral lateral nucleus of a thalamus.
So when we have all this tonic activity in the internal segment of the globus
pallidus we can expect there to be. Profound inhibition in the VA/VL complex.
And without activity coming out of the motor thalamus, we would expect little
activity if any, being generated by the corticospinal tract neurons of the motor
cortex. So, that's the situation at rest.
Now what about when we have a desire to move, when there's a convergence of
inputs from the cortex into the striatium and that's going to transiently drive the
activity of this striatal nerve. And so that striatal neuron, then is
going to be releasing it's inhibitory neuro-transmitter in the globus pallidus.
So when the striatal neuron is excited, we expect there to be inhibition at the
same moment in time of the internal segment of the globus pallidus.
If we remove the inhibitory lock of the globus pallidus on the thalamus then, the
thalamus is free to have a release from that inhibition.
So, for this reason, we say that the thalamus is what has been disinhibited.
So, the inhibition. Of inhibition has released the thalamus
to fire activity which then drives the output of the cortical spinal neurons.
So, one question I often like to ask is, what gets disinhibited with the
activation of this direct pathway? The answer is that it's the thalamus that
gets disinhibited. And the logic there is that the thalamus
is at the end of this two neuron chain that puts two inhibitory neurons back to
back. And that's the circuitry of the direct
pathway. Okay, now let's put together the direct
and the indirect pathway and see how they function.
The direct pathway, as I just illustrated for you, facilitates the activation of
the frontal motor cortex. The indirect pathway works to suppress
the activation of the motor thalamus and, therefore, the output of the motor
cortex. So, the indirect pathway then, would
reinforce the tonic inhibition that clamps down the activity of the motor
thalamus. And here's how this works so let's focus
now on the indirect pathway. So the indirect pathway again is here on
the left side of the figure. We imagine that there are some striatal
cells that are being driven to fire action potentials by input from the
cortex. Those striatal cells send inhibitory
projections to the external segment of the globus pallidus.
This means that the tonic inhibition of these cells in the external globus
pallidus is transiently suppressed. Well, when that happens, then we expect
there to be an increase in activity in the subthalamic nucleus.
So in the indirect pathway it's the subthalamic nucleus that is disinhibited.
That will drive activity, releasing excitatory neurotransmitter in the
internal segment of the globus pallidus. So, what would happen if we increased the
output of the internal segment? Well, that's going to drive up the tonic
inhibition of the internal segment on the motor thalamus, making it very unlikely
that the motor thalamus would send a trigger signal to the motor cortex to
release movement. There's also this direct projection from
the external segment of the globus pallidus to the internal segment.
And well, if we suppress the activity of that external segment then we will see a
reduction in the release of inhibitory transmitter.
That too will synergize with the disinhibition of the subthalamic nucleus.
These two connections put together. Leads to an increase in the inhibitory
output of the internal segment of the globus pallidus.
So you can see how the connections through the internal segment work to
suppress movement. They work in a push-pull fashion with the
direct pathway that converges on the internal segment of the globus pallidus.
With the direct pathway facilitating the expression of movement and the indirect
pathway, suppressing, movement. Now if you're following all this you
should be wondering at this point, well, how is it that we ever make movement, if
these two, parallel streams through the circuitry of the basal ganglia seem to be
fighting each other? Well that's where dopamine comes in.
So let me just highlight the importance of dopamine for the funtion of the basal
ganglia. And something really interesting is
happening here. Dopamine is a biogenic amine
neurotransmitter which is synthesized and released in the striatum.
And it binds to two different types of receptors, their both metabatropic
receptors but they link to second messenger systems that produce opposite
effects on the level of cyclic AMP within the post synaptic neurons.
The D1 receptors lead to an elevation in cyclic AMP, so when D1 is activated
cyclic AMP levels rise. And that has a facilitatory effect on the
post synaptic neuron. When the D2 receptors are bound by
dopamine that leads to a reduction in cyclic AMP levels and that leads to a
suppression of neuronal activity in the postsynaptic cell.
So dopamine is a key regulator of the responsiveness of the post-synaptic
neuron to the input that it recieves from the cortex.
And that post-synaptic neuron is going to be a median spiny neuron of the striatum.
And here's what's important to understand about this.
The D1 receptors. Are expressed by neurons of the striatum
that are in the direct pathway from the striatum to the eternal segment of the
globus pallidus. The D2 receptors are expressed by
striatal neurons that are in the indirect pathway.
From the striatum indirectly to the internal segment of the globus pallidus
so when dopamine is released in the striatum, here's what happens.
The activity of the indirect pathway striatal neurons goes up.
And the activity of the indirect pathway striatal neurons go down, and when we
activate the striatal neurons of the direct pathway movement is facilitated.
When we suppress the activity of the indirect pathway it synergizes with the
activity of the direct pathway. So, dopamine turns this tug-of-war
between the direct and the indirect pathway into a synergistic function where
both of these circuits are now working together.
So it's so important for you to settle in on this figure and understand why
dopamine makes this all work. Well it may be difficult for you to do
that with the complexity of this figure, let me give you a suggestion on how to
approach your studies. Why don't you start with the idea of what
does it take to move the body. Well the cortical spinal neurons of the
motor cortex have to engage our lower motor neurons.
Well, start there. And then back into this complicated
figure. And I think it will be much more easy for
you to understand. So let's try that.
Well, in order to activate our cortical spinal neurons, there has to be a trigger
signal from the thalamus. Well, how does that happen?
We have to disinhibit the thalamus, because remember, its at rest clamped
down by an inhibitory output from the basal ganglia.
So if we have any hope of expressing movement, then we need to take out the
tonic inhibition. From the internal segment of the globus
pallidus. And that's where the direct pathway comes
in. We inhibit the inhibition and that leads
to a reduction in the suppression of the thalamus, which causes a release a
disinbihition of the VA/VL complex. And activation of our corticospinal
neurons. The indirect pathway will synergize
beautifully in the presence of dopamine, because dopamine is serving to increase
the activity of the direct pathway by binding to a D1 receptor.
But dopamine is suppressing the activity of the indirect pathway by binding to D2
receptors. So, if we suppress the activity of the
indirect pathway, that's going to lead to an increase in this inhibitory output of
the external segment of the globus pallidus that will contribute to the
shutting down of the internal segment of the globas palitus.
Which will facilitate movement. So the internal segment is being
suppressed by this direct projection. And the excitatory drive on the internal
segment from the subphalamic nucleus is being shut down.
So, you see, in the presence of dopamine, the direct and the indirect pathway
become synergistic partners for the facilitation of movement.
And we'll talk about, in just a few minutes, the impact of Parkinson's
disease, which involves a loss of dopamine.
And I think now you should appreciate how important dopamine is for the synergistic
function of the circuitry of the basal ganglia.
And hopefully that gives you some insight into the problems that we would face if
we didn't have enough dopamine to shift the balance in activity in favor of the
direct pathway in the expression of movement.
Now, what I've been illustrating for you is the circuitry involved in the, the
body movement loop or the dorsal processing stream through the basal
ganglia. Something quite similar is happening for
the ventral stream. There are direct and indirect pathways
that are running through these ventral parts of the basal ganglia, I won't show
that for you. here, but I do want you to know that it's
occurring in exactly the same way as we see for the body movement loop.
It's just running through different parts of the basal ganglia, through the ventral
striatum and the ventral palladum and then out to a different thalamic nucleus,
which relates back to a different division of the cortex, the pre-frontal
cortex. Okay, we have come to our next pause and
so let's go ahead and take a short break and then please do come back and we'll
pick up with the third part of this tutorial, where we'll talk about normal
and abnormal modulation of movement by the basal ganglia.
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