The indirect pathway does suppress competing movements, and it’s crucial for selecting the correct motor program while inhibiting others.
But here's the nuance:
Think of dopamine as a modulator, not just a switch:
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THIS IS A VIDEO TRANSCRIPT WHICH I HAVE NOT SIFTED THROUGH/ CORRECTED YET
Now we turn our attention to the basal ganglia or They're also commonly known as the basal ganglia. Our next objective for this section of our lecture are to describe. The structure and the function of the basal. Yeah. And describe the role of the substantia nigra, which is a part of the of the basal ganglia in mediating motor and non motor functions of the brain. And then we also want to discuss the development of motor and non mortal deficits that are associated with substantial nigra dysfunction as well as. In general, basal ganglia dysfunction. So let's start with an anatomic consideration of the Basel nuclei, or the basal ganglia. And this is basically revision for you because I know you've done this in your neuron acne lectures. The base on you, clay, are also commonly referred to as the basal ganglia, which is actually a misnomer, really, because a ganglion in the strictest sense is in its definition is a collection of soul bodies, or neurons in in the peripheral nervous system. And the equivalent of that in the central nervous system we know is a nucleus, so these are more appropriately called basal nuclei, but you'll find that so many of the referent texts, some of which you may find as well as Internet resources, may use these two names interchangeably. And you should note that they're referring to the same thing. But basically, the basal ganglia are a network of nuclei that are found deep within the CEREC. From. And in the diencephalon as well as in the mesencephalon, maybe should we say at the border of the mesencephalon and the diencephalon and they include the coded nucleus and putamen, both of which make up the striatum and the striatum is the major input area of the network. Which receives information mainly from the court. Like. And then the other nucleus that you find in the basal ganglia is called globus pallidus. And Globus pallidus is made-up of an external and an internal segment, so there's global, globus pallidus, interna, there's globus pallidus externa and then we have the subthalamic nucleus. And then lastly, we also have the substantial eyebrow. So. Perhaps let's have an overview of what based on your clay actually do before we we look at the actual Neuro Secretary of the basal ganglia. So. The general functions of of your based on your play include control of voluntary movement, control of posture, control of muscle tone, reflexive and muscular activity and eye movements are also controlled by the basal ganglia and control of other. Non motor functions of the brain. This function. And. In our day-to-day lives, like the importance of these functions in our day-to-day lives, cannot be understand and estimated. You will agree with me. That if that fellow that is right at the top there. Who is taking a stroll down to the river and has happened to just disturb the hippo that was having his lunch and doesn't look too happy about it and. Is about to give him a very good chase. The initiation of movement in that fellow there is a matter of life and death, and so too is his control over his velocity of movement or his timing and pace. And. Imagine if he's running away from from this hippo, and then a little bit further down he meets another one or another head of hippos ahead of him. He has to quickly reprogram his movements. And 10 is erection while in progress, and all of this is facilitated by the basal nucleus. So the basal nuclei. Are responsible for controlling movement. First of all, initiation of movement is made possible by the basal nuclei. The patterns of movement are regulated or controlled by the base on your clay, so your timing and scaling of movement, how fast you run, your pace and everything is controlled by the basal ganglia. And then there's also the third aspect, which is programming and correcting movement while in progress. That is also mediated by the basal ganglia. And then you also have the control of posture. Control of orientation, posture, balance, and you can imagine how that is important to that ballet dancer there who is carrying out their routine. So what is called the writing reflex is controlled by the base on reclaim and the base on your clay. Also control automatic associated movement. Which is working. How we set pace to our work and how we control gate. Right. And then the next thing is the control of muscle tone. And you will remember the reticulospinal and the vestibulospinal tract from our other lecture on upper motor neurons and descending pathways. And these control posture and balance. And they are regulated also by by the Basel nuclei. And then you also have the control of muscular, reflexive, muscular activity as well as saccadic movements of the eyes. All of those also controlled by the basal nuclear. Then last but not least, recent research has disproved the long standing dogma that Basel nuclei are only involved in. Model function. And we have actually realized that the basal nuclei are also involved in other non moral functions, for example consciousness, emotions, behavior, particularly behavior that is related to motivation. So those are the general functions. Of the basal nuclei. Of the network of nuclei that we've described that make up the basal ganglia network, the substantia nigra is a modulator of these basal nuclei function. So we're going to pay a little bit of more attention to it and we'll actually consider a clinical. Application of where substance the substantial nigra is damaged a little bit later in this section of the lecture. So the substantial nigra is so-called because of its dark appearance due to the presence of a dark. Pigment that's known as neuromelanin in its in itself. So the substantia nigra is located in the mid brain and it consists of two. Functionally distinct regions. Which are the substantia nigra parts compactor? And this is in the dorsal medial aspect of the substantia nigra, and it has got dopaminergic neurons. Right. And it is actually the principal source of dopamine in the striatum. All right. That projects the stratum, and then we've got the second region, which is called the pause reticulata and the pause reticulata is in the ventrolateral aspects of the of the substantia nigra and it is basically a Gabaergic Gabaergic region. The substantial nigra modulate motor movement through 2 pathways. We have what we call the direct pathway and the direct pathway facilitates desired movements whilst the indirect pathway, which is the alternative pathway, inhibits undesired or competing movement. So we want to look into these levels of control of moral function and combine that with what we already know with what the cortex and the brainstorm and the lower motor neurons do. So the functions of the direct and the indirect pathways. Can be summarized this way. So we have. The pre mortal cortex, where the plan of a desired movement is created. And then we have the primary model codecs where the movement is going to be executed from. And then the plan is made in the pre model, correct? And it is run through the basal nuclei via the thalamus. And then the appropriate model program is going to be activated through the direct pathway, which is that green pathway there. And. Any unwanted model programs are going to be inhibited through the indirect pathway. So that in the end, all competing model programs are inhibited, whilst the appropriate or desired model program is the only one that is stimulated. So what basal ganglia basically do is to refine movement so that you only have the appropriate and desired. Movement occurring and any other movements that may be triggered are inhibited. Alright. So that is the summary of how the basal nuclei or the substantia nigra included, modulates. Modulates moral function. So now let's take a quick look at the direct part. The indirect pathway is not very different and in the indirect pathway, information begins in the cortex and ends in the cortex, so again it is a circuit or it's a loop. So the cortex activates the striatum, which releases Gerber, but this time onto the external segment of the globus pallidus. The globus pallidus externa, the Asterix on the globus pallidus externa, shows that it is tonically active, hence it releases. Garber tonically to inhibit the subthalamic nucleus. So when inhibited by the striatum, that inhibition is removed and the subthalamic nucleus becomes activated and it can produce glutamate onto the output. Plane again, the output nuclei are tonically active. As we said earlier and. Because of that, they produced Garber onto the thalamus, which inhibits the thalamus. So if the output nuclei are activate activated further, sorry by the subthalamic nucleus by production of glutamate, they are going to produce even more Garber onto the. And this further inhibits the thalamus such that the thalamus produces even much less glutamate, as it usually does. That is sent to the cortex, and in that way the indirect pathway inhibits movements. So now we have looked at the direct and the indirect pathway and with that understanding, we now want to add an additional. Fact, which is the fact that the substantia nigra modulates these two pathways and we want to look at the effects of the neurotransmitter that is produced by the substantial nigra. And in this case, we're talking about the substantial nigra parts compact. Which in this case is represented by that green box right in the center. So what you have on that slide is just a combination of the direct pathway, which is the short circuit on the right hand side. And then you also have the longer circuit on the left hand side and that's the indirect pathway. And so the substantial nigra produces dopamine onto the stratum. And one thing we didn't say earlier was that the striatum has got two different types of cell. Of. With different types of receptors and these are the D1 receptor cells and the D2 receptor cells. So those are the two types of cells that you have now. The effect of dopamine on the two types of receptors is actually very different. Dopamine has excitatory effects on cells that have the D1 receptors and has got inhibitory effects on the cells that have got D2 receptors. Cells that have D1 receptors are the ones that mediate the direct pathway. Hence, dopamine will enhance. The direct pathway, whereas cells that have D2 receptors are the ones that mediate the indirect pathway on the left hand side and dopamine therefore inhibits the indirect pathway. Thus, the dopaminergic nigrostriatal pathway, we call it nigrostriatal because it's starting from the substantia nigra going to the striatum. That dopaminergic pathway activates the direct pathway and inhibits the indirect pathway. So overall. It actually enhances the desired movement or activation of the cortex. Through connections similar to those that we've just been looking at the motor circuit, the substantia nigra also controls other non water functions of the brain and these include executive or associative functions such as attention memory. Cognitive flexibility and self-control, and it also controls other emotional or motivational functions such as reward and punishment systems. But what is important to note at this point? Is that the pattern of flow of information is exactly the same as in the direct pathways, that is, from the cortex to the striatum, from the striatum to the pallidum slash substantia nigra reticulata. That's the input areas, and from there to the thalamus, then from the thalamus back to the cortex. So they're all still very much loops, just like the motor loop. But the other thing to note is that the segregation of information. And this happened through topographic representation. You will remember topographic representation, right? So for example, if we're looking at the at the the diagram on the far left, which is the mortar circuit. Information that is coming from the primary motor cortex, that's M1 or the supplementary motor area that's smart or the premotor cortex or the cingulate motor area is projected onto the putamen. Which is the other nucleus that we have in the stratum and. Onto from the Peterman, it is projected onto a different part of. Of the. Of the VA&VL. Of the thalamus. As compared to information that is coming from the front, I fold. Which is projected onto the coded nucleus. Coding nucleus is also part of the stratum and so already we've got topographic representation of information in the Peterman. We've got new clay that receive information from the primary premortal, supplementary and cingulate motor areas, whereas in the coded, that's where we have neurons that receive information. From the from the frontal ifold. Right. And then? From the cordet the information is also projected onto a very different part of the of the thalamus as well. Right. Similarly, information that that comes from. From the dorsolateral prefrontal cortex, which mediates all executive or associative functions, is projected onto the coded nucleus, but a completely different part of the coded nucleus, and also a completely different part or completely different areas of. Off the ventral thalamus, so this is called topographic representation, and it helps to ensure that the. Pathways are actually segregated. You've got a motor path, you've got an ocular motor part, you've got an executive and associative part, and you've got an an emotion slash motivation pathway. All of that happens through. Topographic representation. Yeah. But one thing that is not shown on these figures is the fact that the substantia nigra reticulata also has communication or connections with the superior colliculus and here it helps to inhibit circadian movements of the eyes. Right. OK, so these are the non modal functions of of the Basel nuclei and they are modulated just like the motor pathways. They are modulated by the substantial nigra and the production of dopamine. Our last objective is to look at the disorders associated with based on your clay dysfunction and we're going to look at one example and you can go and look at other examples during your own spare time. So we're going to look at this common disorder that is associated with. Particularly with substantial nigra dysfunction and it is called Parkinson's Disease, Parkinson's disease was discovered by James Parker. Person in 1827 and he described it in his essay on the Shaking palsy and right next to the picture of James Parkinson. I've compared the substantial nigra of a healthy patient, which you can see is very dark and black because of the presence of that. Neuromelanin that we said is present in in in the substantia nigra, but in Parkinson's disease, you'll find that those neurons have been destroyed and they you can no longer find them. That's that dark area is now gone. So that loss of dopaminergic neurons of the substantia nigra. Is what causes Parkinson's disease. So I'm just going to describe the symptoms that are associated with Parkinson's disease. And I would like you to take time to apply the Physiology or the neurophysiology that we now know of how, based on nuclear help in modulating movement and and as well as the motor function principles that we learnt from our previous lecture. Or previous lecture session and we try and explain why people with Parkinson's disease develop these motor symptoms. OK. So. The primary motor symptoms that are involved or that are associated rather with Parkinson's disease #1 tremors. You find that people with Parkinson's disease have got. Involuntary muscle contraction that seems uncontrolled or unregulated. And the question we need to ask ourselves, which you're going to go and and research is why do they develop tremors? What would have happened to their motor control? The other problem they have is akinesia, which is lack of movement or bradykinesia which is slowed movement. And then they also have stiff, inflexible muscles. Or rigidity and the type of rigidity that they have is called cog will or lead type kind of of of rigidities. And again, this is a task for you. Go and find out what is the difference between COG wheel and lead type rigidity and why does it occur in Parkinson's. And then. The the other symptom that is associated with parkinsonism is postural instability. People with Parkinson's tend to have a stooped posture. They have loss of balance, and as a result of that they also have very frequent falls. And practice. And we need to explain the Physiology behind that or the physiological mechanisms behind that. And then the last symptom that we want to discuss is the. Issue of gait. Or walking difficulties. So they've got walking difficulties and they have a typical short and shuffling or freezing gait. So I've put there an image which has got a summary of all the primary motor symptoms that we have in parkinsonism. And as I said, you're supposed to sit down and look at the neurophysiology and neurophysiological mechanisms. UM. Underlying the development of of Parkinson's disease, there are also other non mortal symptoms. People with Parkinson's disease struggle to sleep. They have sleep disturbances. They also have neurocognitive decline and depression and anxiety. And. And quite interestingly, they also actually quite early before all the other motor symptoms start showing, they lose their sense of smell. So they suffer from what we call anosmia or hyposmia. Right. So those are the symptoms that we have in parkinsonism and you will go and look at or rather link the Physiology. And the the pathophysiology of parkinsonism. So just to help you understand how or maybe just to give you a picture of how we ask questions, I've put here a typical exam question or a typical test question that that. Is related to what we've just been talking about, and it is a case about a patient who's showing certain symptoms and is later diagnosed with Parkinson's disease. And you're supposed to explain the physiological mechanisms that are underlying the development of his symptoms, which is basically what I asked you to do. On my previous slide. And together with that, you're also supposed to give physiological explanations of why treatment with a document dopamine agonist would help or not help relieve his symptoms or treatment with an anti cholinesterase would help. Or not help to relieve his symptoms.
“if the indirect pathway inhibits competing movements then why would dopamine inhibit this pathway?”