In today's tutorial, which is, as you know, the concluding tutorial of, unit six. On complex brain functions, and indeed the concluding tutorial of medical neuroscience. I've chosen to wrap up the course with a topic that is of tremendous importance for anyone entering the world of healthcare. Because of the impact of addiction on societies all over the world. And indeed because of the risk of addiction for workers in the healthcare Sector of our global economies where opportunity and risk abound. So I want us to just think together, very briefly, about some of the mechanisms of addiction that pertain to the structure and function of the limbic forebrain, and to do so we're going to back up just a little bit And, talk briefly about the basal ganglia, and the brain's intrinsic system for reward. So, today's session pertains to several of our core concepts in the field of neuroscience. We will, again, talk about the complexity of the brain, and illustrate the fact that the brain is, indeed, the body's most complex organ. We'll be talking about genetically determined systems, and circuits, that provide the foundation for the function and operation of the central nervous system. And in this case, we'll be focusing on the brain system for reward. And then lastly, the phenomenon of addiction is a sad but compelling demonstration of how life experiences can change the nervous system. And the challenge for medical science and for rehabilitation professionals is to understand best, how do these intrinsic systems of reward operate in the brain? And how might we best approach the process of undoing the grip of addiction, that can come upon the brain's intrinsic reward system? So my learning objectives for you, in this tutorial our first to be able to discuss the brain's reward system and next to discuss the involvement of the limbic fore brain in mediating addictive behavior. Now, as we get into this topic, it will be clear that one very important brain system. That is germaine for understanding addiction is in fact a component of a brain system that we've already spent a fair bit of time wrestling with. And that is the basal ganglia. So I'll remind you that there are multiple streams, or loops, as we sometimes call them that run through the basal ganglia. We talked about a dorsal motor stream, or a motor loop, that principally runs through the dorsal parts of the basal ganglia, that is the putamen which is a major component of the striatum, lateral to the internal capsule. The putamen has important connections to the globus pallidus which then projects to the motor thalamus that modulates The expression of movement, specifically the initiation of movement or the suppression of movement. We talk briefly about a cognitive stream that runs through the caudate division of the stratium, the caudate nucleus. And this caudate nucleus has projections into the Pars reticulata component of the substantia nigra. That's a palatal region that serves the anterior part of the head of the caudate nucleus, and it's involved in this cognitive loop that involves movements of the eyes, as well as movements of the mind. As I've mentioned several times, what we look at is often what we are thinking about. And, that can become the object of our plans for future actions. Now, in this tutorial we're going to focus on the third major division of the striatum, the Nucleus accumbens, which is an important component of what we've called the Ventral striatum. And this ventral striatum has the same kind of circuitry that we've seen in the other divisions that is a direct and an indirect pathway. But it's operating upon inputs that are coming from different parts of the telencephalon. And the output from the palatable component of this striatal loop is directed towards a non-motor thalamic nucleus namely the mediodorsal nucleus of the thalamus which then projects into our prefrontal cortical networks. So let's take a closer look at this ventral-limbic loop in the basal ganglia. And that will help us understand a little bit more about how our reward system might be operating in the human brain. So as we see this limbic loop really begins with inputs that are derived from. Regions of the telencephalon such as the amygdala, the hippocampus, the orbital frontal portion of the prefrontal cortex, the cingulate gyrus and even the cortex at the anterior pole of the temporal lobe These are all important integrative associational areas, that are involved in the experience of emotion. And the integration of emotional experience with other dimensions of cognition. So these are the sources of telencephalic input into the ventral striatum. And specifically what we're talking about here is the major component of the ventral striatum is the nucleus accumbens. You'll recall that this is the division of the striatum that is continuous with the caudate nucleus dorsally and medially and with the putamen laterally and dorsally. And this nucleus accumbens wraps right underneath the white matter of the internal capsule. So here's the internal capsule, and we see that on either side of the internal capsule are components of the striatum caudate medially, putanum laterally. And then inferior to this internal capsule's where we find This nucleus accumbens. Now, the nucleus accumbens, the ventral striatum, then sends inhibitory projections into the pallidum. And the pallidum that we have in mind with our ventral limbic loop is called the ventral pallidum as well as the reticula component of the substantia nigra. So the ventral pallidum is a region just behind this section, we can't see it in this view. It's a region Posterior to the nucleus accumbens, but inferior to the globus pallidus, so it's a much looser organized reticulated network of pallidal neurons. While the output from this ventral pallidum and this particular component of the pars reticulata is directed at that medial dorsal nucleus of the thalamus. Which is the principal thalamic nucleus that projects out to the prefrontal cortex. So the projections here are indeed directed back towards many of the same Cortical regions that gave rise to input to this nucleus accumbens in the first place. Most importantly, the orbital and medial part of the prefrontal cortex. Now what we've illustrated here is the direct pathway through the ventral limbic loop. And I hope you've recognized that based on the presence of these two inhibitory connections within the basal ganglia circuitry, that when active serve the purpose of disinhibiting the thalamic projection to the cortex, and that disinhibition then provides a kind of a go signal. For the engagement of the cortical circuits that are responsible for some kind of shift in behaviors. So exactly what kind of behaviors we have in mind is going to depend on what is actually being integrated in this cortical network at the time. But we can imagine that that has something to do with affect, with emotion- With mood. Perhaps even the kind of shift in affect that we would associate with the presence or the prediction of a reward. That is, we know something good's about to happen, and there's some kind of a shift in our emotional set. And, it's that shift played out in this circuitry of the orbital medial prefrontal cortex, that we think is really the instantiation of a rewarding experience. Now, in talking about reward we imagine that there is some kind of operation like this that operates For the instansiation of the negative valence that we might associate with this kind of behavior. That is with punishment. Something that has a negative reinforcement property. Also involves a shift of some sorts. So we imagine there's likely to be A different kind of network. probably also in the orbital and medial prefrontal cortex. But maybe in a slightly different location that is responsible for initiating that shift towards the negative valence of punishment or deterrence. Or this Concept that, okay this is a bad outcome, so I need to learn my lesson here and try to avoid this kind of contingency in the future. So hopefully this gives you a sense of how the basal ganglia might actually be key And understanding how the reward system of the brain might work. To either reward with a positive reinforcer, or a negative punisher. Now there's one critical component of this circuitry that I need to highlight before we move on. And that is found right here, on the medial edge of the substantia nigra in the mid brain. This is the ventral tegmental area which is critically important in modulating. The way the circuitry through the ventral loop of the basal ganglia operate. So the ventral tegmental area is the source of dopamine for the ventral part of the striatum. So there are projections from this mid-brain region into the nucleus accumbens. Where dopamine is released. And there are a variety of dopamine receptors. We've tried to keep it simple and only primarily talk about two kinds of dopamine receptors. In the striatum we have D1 and D2 receptors. The d1 receptors are associated with the direct pathway so in the illustration that we have, here to the left we imagine that the D1 receptors are being activated, when ventral tegmental neurons begin to fire and release dopamine Effecting this direct pathway from ventral striatum to ventral pallidum. substantial nigra, pars reticulata and then back to the medial dorsal nucleus of the thalamus. But there is also an indirect pathway not illustrated here for simplicity, where dopamine is going to interast with D2 receptors and suppress the firing of those indirect pathway striatal neuron. And together when dopamine is present the D1 and D2 receptors work synergistically in order to facilitate the activation of the thalamocortical connection.
