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.
