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Nick Jikomes
And what is your lab study? And what are you known for?
Kent Berridge 4:03
Well, we're really interested in understanding liking and wanting things, various kinds of rewards, natural foods and drinks and other natural rewards but also drugs of abuse, and social and cognitive rewards. We're interested in emotion in general and motivation in general, but liking and wanting are probably what we're best known for.
Nick Jikomes 4:25
And so, you know, I think everyone has an intuitive notion of what it means to like and to want something, then these two things are intertwined. They go together, right? Typically, you like things that you want. So let's maybe paint a picture for people of of what's going on, in say a scenario where maybe I just ate a meal. And it was a normal meal at a normal time of day or something. I'm satisfied, I'm full. And then for some reason, let's say I'd go two or three days without eating. So I get really hungry, I can't find food. And then I encountered that. That same me Again, after a couple of days of not eating, walk us through what's going on phenomenologically and in the brain a little bit in terms of, you know, as my hunger builds, and I'm searching for food, and I finally find it, and then I eat it that second time, how was that second experience different from the first experience and what's really going on to account for the change in the two different meals that I eat?
Kent Berridge 5:22
Well, when you're hungry, your brain's mesolimbic system is primed to respond to food cues all around you. So maybe we're walking down the street and the smell of food hits you. And now you really would like to eat and maybe you'd like to eat that particular food that you just smelled. This, these food cues turn us sort of tempt us when we're in states of hunger. And if we taste it will like it, we want and like it, I have to admit, when I started in the field, I thought liking and wanting were basically just two words for the same process. We're headed to change your mind along the way. If you taste of food, just one little taste of food, you can find even more appetite. So you may have this cocktail peanut phenomenon where you eat one to be polite, but now you'd kind of like another peanut that can prime you. But as you go on and eat more and start to trigger post injustice, satiety cues, then the pleasure can decline a little bit over the course of a meal. And if you're really stuffing yourself at a major feast, you may at the end just not want to see another piece of food. So you can change absolutely changed both how you like and want the food on based on your state. Now go for a couple more days and it may start to appeal again. So Prime's you again.
Nick Jikomes 6:42
And so, so when I eat that second meal after I'm really hungry, you know, it'll probably taste different. It'll be the same basic flavor profile, but I'll like it even more, because I'm really hungry the second time I encounter it compared to the first time. So what what's actually happening in the brain and why is this happening that that the tastes are going to be more pleasurable or be more pronounced and how I feel them?
Kent Berridge 7:05
Well, it's a phenomenon that was recognized by Aristotle. So it goes way back 1000s of years. But the modern term for it is Alia, seizure. This was coined by Michel Cavanagh, a French neuroscientist, and psychiatrist working in, in Leone, originally around 1970. And he sort of pioneered the scientific study of pleasure and changes in pleasure that were induced by changes in physiological state, so that the pleasure of food can absolutely vary, depending on your hunger and satiety and familiarity, the pleasure of temperatures on a hot on a hot day, you might enjoy a cold swim a cool full width on a cold winter day here in Michigan, you'd probably prefer a hot shower, this changes in the pleasantness of thermal temperature sensation happened to and lots of lots of pleasurable sensations can be modulated by physiological state. This is Alia Stasia. It's a word that means change in sensation, although it's really just a change in the pleasure of the sensation, other parts of the sensation stay the same and stable.
Nick Jikomes 8:10
And so you mentioned that there, there apparently, is this difference between liking and wanting something. So even though even though these two things go together, often, they're not the same thing. So what are maybe some examples where an organism wants something it doesn't like or like something it doesn't want,
Kent Berridge 8:26
right? Well, to kind of recapitulate, I originally did think that liking walking with a saint. And in neuroscience, especially rising as a theme in the 1980s was originally the notion that pleasure in the brain was mediated by brain dopamine systems, mesolimbic dopamine systems, and it's still sort of synonymous and famous for for pleasure and rewards. Even today, the notion that it was specifically the pleasure of rewards this was a an idea championed by Roy Wise, who was then in Montreal at Concordia University, and he had many clever experiments where he would mildly impair dopamine function in rats, usually, with a drug that blocks dopamine receptors, neuroleptic or anti psychotic drugs that block the two type dopamine receptors. And we just give a mild to moderate dose of this if you give a strong dose, you suppress all behavior and motivation. But if you give a mild dose, what he found was that the rats would pursue initially the rewards of all kinds just as much as they were ordinarily would. So if they learned to run in a maze for food, they'd run eagerly for food the first time if they were working for say, brain stimulation rewards, you know, electrode rewards in the lateral hypothalamus that turn on dopamine systems. If they if the rat presses a lever they would do that originally is with enthusiasm too. But if you let them keep doing this and experiencing the rewards under the dopamine blocking drug effects So what he found was the gradual diminishment, so they started to cease to persist, they would just sort of give it up. And this looked a lot like what would happen if you would just turn off the reward midway while they were working. If you turned it off, they'd gradually extinguish it's called extinguish, because they're not getting the reward anymore. They'd extinguish. They're, they're working for those rewards in their consumption. And he thought, the pin beside that these neuroleptic drugs that block dopamine, were doing the same thing causing this extinction. Mimicry he called it. And the best way to explain it he proposed was, it was like, extinguishing, like removing the reward. Basically, it was removing the pleasure of the reward. And they were finding that even though they were still getting the food, or they're still getting the electrode, it was no longer pleasant. So they gradually abandoned it. This was the dopamine pleasure hypothesis. Based upon these dopamine, what he called Anhedonia experiments, were the drugs seem to drain away the pleasure of all these rewards. And I was totally convinced there was a number of clever details that he embedded into these experiments to rule out some alternatives, like was it just impairing their motor ability to move and pursue the rewards? No, it wasn't just that it seemed really specific. So they didn't want these rewards anymore, apparently, because they didn't like them anymore. That was the inference. And it seemed convincing. I actually got into this issue by an a collaboration with Roy wise, because my lab here at Michigan I had just recently started in the mid 80s, was looking at pleasure in the brain from a slightly different way and a different method. Rather than ask individuals to pursue and work for rewards. We were using a method that's kind of similar to what human parents have used for eons to ask their newborn babies, do you like the taste of foods that we eat by giving them just a little sample of the taste and watching what they do? You know, if it's sweet, it's nice, the baby made sort of like
an swallow. And if it's a bitter taste, the baby will gape sort of triangular, opening up the mouth, screenshots, eyes, shake its head, weight, its arms. And this is a difference between liking and disliking. While we were doing this with rats, and looking at brain mechanisms that might change liking and disliking, because it turns out that rats, which are omnivores, they like sweet, fatty foods, just like we do, and they don't like bitter foods, they have some of the same facial expressions if you infuse the taste solution into their mouths, Roy wise called me in the mid 80s, and said, Why don't we collaborate. And he sent a graduate student from Montreal down here to Ann Arbor, Michigan. And we did a collaborative experiment where we gave his neuroleptic, dopamine blocking drugs, to rats, just before we infuse sugar solutions into their mouths. And we expected their liking reactions to go down. That would be and he don't, you know, just one more little piece of evidence on the enormous pile of dopamine is pleasure evidence that we always had accumulated. That was my hope, that we'd find that we didn't find that the drugs didn't change the facial expressions of liking at all. And I thought, well, we just maybe did the experiment wrong. It was my first experiment with dopamine blocking drugs. It was the graduate students first experiment on these facial reactions. And maybe we just did something wrong along the way. So I repeated this experiment several times in my lab and use different dopamine blocking drugs, and always got the same result, it didn't change the liking reactions. And at that point, I thought, well, maybe drugs just aren't strong enough. We need to do something stronger to prove this dopamine pleasure hypothesis. So what I did was to collaborate with my colleague here at Michigan, Terry Robinson, who was looking very closely at brain dopamine systems. And he was looking especially at their role if he lesion the brain dopamine system, selective lesion that could eliminate brain dopamine, but preserve every other neuron intact. These are called Six hydroxy dopamine lesions. Six hydroxy. Dopamine is a neurotoxin. If you do a micro injection of this neurotoxin, into the medial forebrain bundle around the hypothalamus, where dopamine neurons are sending their axons up towards their targets, you can hit all of those dopamine neurons and this toxin just kills the dopamine containing neurons leaves other neurons intact. We eliminated 98% 99% of dopamine fibers going up to the nucleus accumbens and striatum with these neurotoxin injections. This creates a sort of severe Parkinson's disease like state in the rats, they will never voluntarily eat, they'll never voluntarily drink. We can keep them in good health by giving them artificial meals and hydration the way you and I would be fed if we were in an intensive care in the hospital. And we would do this and then we could ask them now finally, our is liking for sweetness gone? And the answer was no, it was absolutely normal their liking reactions to the sweetness, we asked Could they still learn new likes and dislikes. So we would take us a new sweet taste that they had never tasted before sacrum and poly Coast mix together. It's kind of distinct from sugar. But the rats like it, we would pair that new sweet taste just three times with nausea induced by lithium chloride injection. This creates a learn taste aversion in normal rats and many people develop learn taste versions for new tastes that are paired with nausea. It creates a disgust sense that tastes subsequently if the brain is processing correctly. And it did in these rats who had virtually no dopamine, maybe just one to 2% of their natural dopamine remaining, they still had new normal likes, and they could learn new dislikes or new likes at all seemed normal. It despite their massive deficits of not reaching out and not eating voluntarily not pursuing any reward at all. And we were left scratching our heads and saying well, how can we explain this we thought this was going to eliminate dopamine is pleasure. And these pleasure reactions are still the same. That's when we began to think well, what if dopamine mediated the wanting for these liked rewards but wasn't necessarily for the liking, per se? What if the brain kind of separated these two sides of the same coin these two words that we thought were the same psychological process? The brain might be telling us? No, they're actually different psychological processes. That was the beginning. There were many subsequent experiments that kind of probe that further, we would turn on dopamine and see if Could we turn on wanting without turning on liking? The answer was yes, we could, in many cases, many ways. That was the beginnings of that hypothesis.
Nick Jikomes 16:51
I see. So the idea originally, and you still you still see this believed in Popular Science a lot these days was pretty much dopamine equals pleasure. So whenever you taste something you like, or you get a drug that you like, that makes you feel good. That's mediated by dopamine, what you're saying is they did these experiments back in the day, they were able to pharmacologically block dopamine in the brain. And animals seem to be less motivated to get things that they liked. The idea was that they must, the liking part of it the way the goodness that they feel, presumably, is lower. But then you did these clever experiments where you can destroy all of the dopamine neurons, or nearly all of them, that destroys their motivation to go and find things they like. But then when you put something that they like the taste of right in their mouth, even though they're not motivated to go and get it themselves, they still respond behaviorally. With the same way, they still seem to like the taste, even though they're not motivated to work with it.
Kent Berridge 17:48
That's right, they still show all the same facial liking smack lip, smacking your lips, licking their lips, that they would if they if it was absolutely normal. And that was such a disappointment to me originally, it wasn't the result I wanted. But was the result that the observations seem to force upon us at least as a possibility.
Nick Jikomes 18:10
And so you know, it's interesting, you said, you know, rats and mice will have these facial expressions, and infant children will have them. And so does that mean that, you know, some of the some of the things that we experienced in terms of what we like and what we don't like to taste are hardwired and innately specified?
Kent Berridge 18:30
Well, I think they are, these are brain systems that evolved originally, eons ago, dopamine neurons, and some of the basic circuitry has been argued to be almost 600 million years old by some neuroscientists who say that the same dopamine systems might be found even in arthropods, like insects and crustaceans, to some extent, now, that's a controversial hypothesis. But it's very clear that in mammalian evolution, at least, these are very ancient brain systems, we have them, rats have them, virtually all mammals have them. And they seem to be operating in similar ways, you know, all of us.
Nick Jikomes 19:10
And it makes sense like that we would naturally like something sweet that has sugar in it, because of the way that our metabolism works, right? These those are going to signal things in the environment that have calories that we'll need. And so so naturally, it makes sense that the brain would, you know, create a positive emotion, a feel good emotion to motivate us to get those things. sort of the opposite with bitter things. But we can also learn to sort of overcome this, right? Like, I remember being a kid and trying coffee at some point and thinking, Oh, this is gross. Why does anyone drink it? Then as I got older, and I was in college, and they needed to wake up in the morning and go to class and everything, I learned to overcome that natural aversion to the bitter taste of the coffee and I learned to like it. So what's going on there when an animal learns to like something that previously didn't like?
Kent Berridge 19:57
Well, we absolutely can learn new likes and dislikes. for coffee for alcoholic beverages for some people, even tobacco smoke, noxious all of these originally, but learned, wants and learn likes can definitely happen. The reason this can happen is because the liking for something, it's never inherent in the physical stimulus itself, completely sweet things are liked ordinarily, but they can become disgusting if they're paired with illness in this way, and disgusting things can become liked. What's happening is that the brain has liking mechanisms absolutely does. Turns out that dopamine is not the major linchpin in the liking mechanisms. But these liking mechanisms can come on and create sort of the lightning gloss this hedonic loss on the taste of coffee. They easily and naturally do it to the taste of sugar. But it's these systems coming on these liking mechanisms that generate intense liking, call them hedonic hotspots in the brain, the ones we've found so far, they are putting the pleasure on it. So it's really a question of what's activating these mechanisms they can learn to come on, they can learn to not come on. That's
Nick Jikomes 21:13
so So is it fair to say that we used to sort of equate dopamine with pleasure? That doesn't seem to be the way things work? Is it fair to say that dopamine is more to do with the motivation to to do things and to behave and to go out and get things?
Kent Berridge 21:29
I think that's the best way to put it exactly. But I have to admit, you know, dopamine is turned on by pleasure. So I'm in all kinds of sensory pleasures in animals and in humans for foods and drugs, and sex and brain stimulation that is rewarding turns on these dopamine systems. And there's evidence in humans that even cognitive pleasures, like listening to music for people who really enjoy music can turn on dopamine systems as well, looking at the face of a loved one can turn on dopamine systems. It's turned on by pleasures in so many situations, so it correlates with pleasure. Absolutely. The question is always just is it also causing that pleasure? Or is it caused by the pleasure and now it's causing the motivation for that pleasure? That's the distinction that our results pushed us to
Nick Jikomes 22:18
initially, I see for the hedonic component of this, the actual liking or the pleasure that you feel when you you find something that you'd like whether it's food or something else, is there like another transmitter system that does seem to be causally related to the liking part of it?
Kent Berridge 22:33
Yes, there is. Opioids, natural brain opioids like and Katelyn endorphin can do it. Obviously, opiates and opioid drugs, like heroin or fentanyl can do it. They activate new opioid receptors, and in particular locations of the brain. These mu opioid receptors, if they're activated, can cause pleasure like and can intensify the liking. Now, it's not throughout the entire brain. It's not even throughout the entire reward structures, say like the nucleus accumbens is a famous reward structure. And within the nucleus accumbens, there is one little spot I'll hit on a hotspot that's about 1/10 of the total volume of the nucleus accumbens at the very front and sort of middle on both sides and top of the nucleus accumbens shell, this heat on a hot spot, if opioid stimulation is given to it inside their neurons that have these opioid receptors, this enhances the liking. So this will generate increases in liking and if we eliminate this sort of thing, it can induce like, other neurotransmitters to like endocannabinoids in the same hedonic hotspot, the sort of brain version of of marijuana, THC, your neurotransmitters like anandamide, for example, can turn on liking in the same heat on the cosmos. There's a hedonic hotspot in the nucleus accumbens, about 1/10 of its total volume. In the orbital frontal cortex, that's a part of our cortex just above the eyes. There's another hedonic hotspot, just a small zone of it about again, about 10 20% of that orbital frontal cortex. There's another in the insular cortex, this sort of tucked in on the sides of the brain, the back of the frontal lobe covered up by the temporal lobes. The insula has a hedonic hotspot. And there's a couple of depths sort of lower in the brain below the nucleus accumbens, like in the structure called the ventral pallidum. That's especially important for pleasure and even one perhaps in the brainstem. So there's several of these hedonic hotspots, opioids endocannabinoids, a couple of other neurotransmitters in them can turn on the liking. Dopamine never, ever does. If we move out of the hedonic hotspots, if we give opioid stimulation say to the 90% of the nucleus accumbens, that isn't the hedonic hotspot. What that does is it turns on wanting for rewards just like dopamine does, but it does not turn on the liking. So it's sort of a combination of opioids in the hotspot that intensify lightning. The brain has kind of dismissed drifted liking mechanisms, more massive wanting mechanisms when liking does come on. So if we do stimulate a heat on a hotspot in the nucleus accumbens, it turns on the other heat on a consequence, recruits them into CO activation. So they all come on sort of like a unanimous network. And if that happens, when that happens, that it causes the intense liking. If we disrupt that unanimous activation, then liking isn't enhanced. So these are mechanisms that can give pleasure or take it away.
Nick Jikomes 25:31
And so I suppose, you know, when we start talking about things like opioid receptors, and other things, they are directly involved in the liking of things they are distinct from but but sort of working with, in a sense, the dopamine system that underlies the motivational side of this. So how do we start to think about addiction here, it would make sense that something like an opioid would be very pleasurable and euphoric, given what you just told us. So you know, what's going on in the brain as you try something like an opioid or an addictive drug that you like, and then you proceed to a compulsive state where you are constantly motivated to take this even if the effects start to wear off in terms of how it feels,
Kent Berridge 26:11
right? Well, opioids indeed are very pleasant drugs. And that's, of course, why people take them. Now not everyone who takes them becomes compulsively addicted to these drugs. So there's a difference of distinction between drug use and drug addiction. It turns out that relatively a minority of people who are taking say, cocaine or or heroin will become compulsively addicted, somewhere between 10% to 30%. Depending on the drug and how it's taken. These are the individuals who become compulsively addicted. So the question for addiction is really about what's happening that makes those individuals were disposed by genes and by other early environmental experiences and other considerations, what makes what is the switch that flips basically within them to cause the addiction. Now, addiction theories in neuroscience throughout the 80s, and 90s, were really based mostly on the notion of withdrawal. You know, opioids can produce a strong withdrawal syndrome. Of course, alcohol can, if a person is really dependent on alcohol, it can cause this withdrawal can actually be fatal by inducing convulsions that can sometimes be fatal. So withdrawal can be very potent. On the other hand, some drugs that are really quite addictive like methamphetamine and cocaine, they produce at best only weak withdrawal syndromes compared to heroin or alcohol. And even for the drugs, that they've can be very addictive. These methamphetamine, cocaine for the for the particular individuals. And even for drugs like heroin, or fentanyl, it's very famous that you can take people who want to give up their addiction, who want to give up the drug, keep them in a drug treatment center, get them through detoxification, get them through withdrawal. So withdrawal fades and leaves them behind. Then they go back into ordinary life and relapse, again and again, after months, or even years of abstinence, but yet relapse, find it irresistible at some point. So withdrawal is potent. But it may not be the essence of addiction and sort of relapse in the absence of withdrawal, or kind of examples of that it's not now I have stumbled into addiction neuroscience theory, really, with my colleague, Terry Robinson, because as we were developing this notion that maybe dopamine was more about wanting things than it was about liking things. Terri Robinson's lab here at Michigan, was studying a different side of dopamine. And that is what happens if you take addictive drugs again, and again, drugs like amphetamine. And it's famous that drugs do produce sort of downregulation of dopamine receptors and opioid receptors, that is, some of the receptors start to go away if a person is constantly taking drugs, and this is what can produce tolerance and contribute to withdrawal syndromes. Some of that comes back if they stop. But there's also another thing that can happen in dopamine systems, much of the withdrawal and tolerance goes away if a person stays off the drug for months, weeks and months afterwards. But a second thing that can happen in dopamine systems, especially of some individuals who are predisposed to the second thing is called neural sensitization. And what that means is that if, if the individual takes drugs again and again, especially if they sort of spaced this apart, so like taking weekend binges of the drug, but not so much every day during the week, spaced apart, beams like doses in vulnerable individuals create what's called neural sensitization of the dopamine systems and what it looks like what it how you see it, is that the dopamine neurons that release dopamine when you take amphetamine or cocaine or other drugs, they start to release more dopamine on the 10th, same time with a 20th time than they did on the first time, even though the dose of the drug is the same. So becoming hyper responsive, hyper reactive to the drug, the dopamine neurons change, they release more dopamine, the neurons they talk to that have dopamine receptors, they change and they can become hyper reactive. So the circuit kind of becomes hyper reactive to this dopamine influence. Now, it doesn't happen to everyone. Again, genes and other
factors like stressful experiences previously, can dispose one towards this. If it happens, though, if it happens in the individual, it tends to last long, long, long. After even after they stopped taking the drug, it lasts about half a lifetime in a rat. In a person, we know it lasts at least two years, and it may last half a lifetime in people in the vulnerable people get sensitized. Now, if we take the notion that some people might get sensitized to addictive drugs, and to have a hyperactive dopamine system, and combine that with the notion that maybe what dopamine is doing, psychologically, is not so much the pleasure of these drugs or other things, but the wanting for them, then you can come up with the idea that a sensitized addict might be someone who has hyper wanting sort of excessive wanting that certain follow certain psychological rules we know about, even if they don't like the drugs, even if their liking is the same as it was in the beginning, or even if they're liking has declined over time, they'll still have this excessive wanting for for the drugs. That was the notion that we offered as an addiction theory called the incentive sensitization theory of addiction for that in the 90s. And it's probably safe to say that nobody believed it.
Nick Jikomes 31:48
And so when we think about, you know, sensitization in vulnerable, vulnerable people, people who are predisposed to becoming addicted to addicted, addictive drugs, how specific are these? Are these effects? Is someone specifically going to be predisposed to being addicted to a psychostimulant or an opioid but not both? Is someone predisposed to become addicted to drugs like this also predisposed to developing, say, you know, eating disorders or becoming addicted to non drug rewards like how general is the system?
Kent Berridge 32:22
Well, in one way, it's quite general, and in a different way, it's quite specific in the way it's general is that many drugs can induce sensitization. And once it's induced by one, the system also often shows what's called cross sensitization to the other that is, it responds in a sensitized fashion to the other, even though the other might just be taken for the first time on this occasion. So it's generalizable in the sense that there is cross sensitization. On the other hand, this system can become psychologically very specific in its target. So it isn't that a sensitized person wants everything in life, that their motivation rises, like a rising tide floats all boats, so there was everything, career and family, as well as drugs, it gets narrowly focused, it can get narrowly focused, and so that only this one thing is wanted. So a person might only want one kind of drug or only a couple of kinds of drugs, for example, general inputs, but kind of a neuro psychological output.
Nick Jikomes 33:20
And so when you think about something like drug addiction, how analogous is that to the notion of a food addiction, or people just binge eating and becoming obese? Because there's lots of tasty food around that's constantly tempting them? Is it? Is there a lot of overlap in the mechanisms there? Or was there is there like a distinction between these different kinds of stimuli, something that you ingest as food versus something that you take as a drug versus something that you drink? or what have you?
Kent Berridge 33:52
Well, potentially, I think there is quite a room for overlap, at least for some individuals definitely overlap. If you'd asked me 15 years ago, I wouldn't have said that. But what's happened last 15 years are two kinds of things. One is neuroimaging evidence on food addiction and gambling, addiction and such, that suggests the same brain mesolimbic systems are involved and becoming hyper reactive in these individuals say in a gambling addict. So it's drug cues that activate the system, but not say food, whereas in a binge eater who might have what could be legitimately call food addiction, it activates the food cues, but not to the money queues. So again, this this hyper wanting of these particular things. That's one kind of evidence that leads us the notion there might really be overlap. The second kind of evidence is something that happened beginning in the mid 2000s, early 2000s, which was the invention of a new medication for Parkinson's disease. That was a wonderful godsend. It was the invention of what are called direct agonist medications for Parkinson's. The old medication for Parkinson's were was to L dopa. And what l dopa if a person takes it does what it makes neurons in the brain generate natural dopamine, more natural dopamine, even some neurons that aren't making any dopamine. Now, if we take a dose of L dopa, they'll start to make dopamine. So the brain gets kind of a flood of natural dopamine for many neurons that can still make it that was a replacement therapy for Parkinson's. The new medications, the direct agonist medications, they're really more like fake dopamine. They don't need natural dopamine, they can themselves these molecules activate dopamine receptors, but not all dopamine receptors, they activate what are called specifically D two and D three types of dopamine system receptors. There's five different types altogether. And these are two of those five different types D two and D three. And if a person takes these direct agonist medications that activates those receptors, it helps them a lot to with the Parkinson's symptoms. So it's a godsend. But in another sense, it's a diabolical medical experiment, because in about anywhere from 15%, up to say 45% depending on the study you read, of patients who are taking these direct agonist medications, they start to develop compulsive motivations, they that they never had before. So they may develop compulsive gambling, or compulsive shopping, or compulsive pursuit of sex and pornography, in some cases, compulsive binge eating, in other cases, compulsive over consumption of their medications. So they go to multiple neurologists and get multiple prescriptions for these dopamine agonist drugs. And they over consume the drugs. In some cases, compulsive hobbies, like building up something in the garage, but at 3am in the morning, and you can't quite stop. And if a person shows one of these compulsions, they're likely quite reasonably likely to show a second and a third. So it's like a little family of, of behavioral addictions can jump up in the same person while they're taking these dopamine stimulating medications that they never had before. And fortunately for most people, if you stopped taking the medication, or if you at least turned down the dose, the compulsions go away, not not for everyone, but for what usually. So it's really the dopamine stimulation. The fact that this can happen, says first, that dopamine stimulation giving this artificial dopamine stimulation to vulnerable individuals can create addictions. That it isn't that the people have credibly enjoy these things that they're doing. They don't. But they do incredibly want to do that and find a compulsive to do it. They may five be distressed psychologically, because now they think they're a bad person if they're bankrupting their family or pursuing sex in inappropriate ways. But it's a compulsive one, the fact that it can happen is evidence again, that really dopamine stimulation can create wants that don't have to be justified by likes. The second thing it tells us is that there is an overlap between some of these different compulsions because you produce compulsive gambling, perhaps, and compulsive shopping or binge eating in the same individual that says there's an overlap.
Nick Jikomes 38:05
And it's this I mean, this makes me think about something like OCD where you have an obsessive compulsive disorder is that I would guess that's mediated by some kind of increase in what the dopamine system is doing. Is that the case?
Kent Berridge 38:20
Well, it's a good question. And there's definitely evidence neuroimaging evidence that OCD involves sort of changed activation in striatum medial striatum, a nucleus accumbens, these same dopamine targets to the same brain structures and received dopamine suggesting that there could be an overlap there. I, I wonder about this question myself in terms of whether excessive incentive salience excessive dopamine wanting is involved in a compulsion. It is a real possibility that it is. On the other hand, there's another alternative explanation for OCD that's often invoked, which is that it's driven by anxiety rather than wanting to do something, and that the compulsions are engaged in as an attempt to damp down the anxiety. To the extent that anxiety is purely powering an obsessive or compulsive disorder, then we may not need excessive wanting, and we don't we don't know if it's happening, but I don't think we have really good clear insight into whether it's happening yet. It is a possibility.
Nick Jikomes 39:22
And what is the connection between, you know, habits and behaviors generally, and their ability to sort of treat negative affective states like anxiety? Or, you know, how often is it the case that some of these behaviors that animals execute, or some of the habits that people developed, are actually a kind of behavioral treatment for things like anxiety and depression or what's the actual what's the actual connection there between the emotion state that they're trying to get rid of, and the actual behaviors that they're
Kent Berridge 39:51
executing? Well, there are comfort activities. Of course, people may have activities that we engage in to kind of reduce anxiety He's in an adult rats who are stressed or mice where stress may started, they start to groom themselves. So face washing and body washing. And it's thought that's sort of a stress induced kind of potentially activity that helps them to come down in arousal as they're doing it. On the other hand, most habits probably aren't really, most habits, the performance of them per se, are probably are not very powerfully reducing anxiety or even reducing it at all. There are habit theories of addiction in neuroscience today, and going back in psychology to the 1930s that are habit theories of addiction, but generally, they don't invoke reduction of anxiety, they invoke a different kind of process from that.
Nick Jikomes 40:40
And so, you know, it's it's very intuitive and easy to think about things like addiction in terms of going out and getting more of something, you go out and get more of a drug or you go out and you eat more of the food that you like the taste of. But then there's also things like eating disorders, where people, I mean, effectively seem to become addicted to not eating or depriving themselves of something. And so if you think about something like anorexia, for example, do we know what's going on there to get you to this weird place where you, you really seem to want to deprive yourself of something that you would ordinarily naturally be motivated to go and get?
Kent Berridge 41:15
Well, I don't think we can claim that we know what's going on there. This is a topic of study, and we'd love to know what's going on there. I would say, I mean, it's an open empirical question to whether these kinds of psychological processes play a role. And I don't actually study in a row, anorexia nervosa so and I don't have a human patient studies at all. So I'm not in a position to collect the evidence, but other people are. And there are there have been some suggestions that it might be not only a sort of dis, not just wanting a food, but actually kind of an excessive motivational salience attributed to foods. I mean, I've been told by psychiatrists who work with patients with anorexia nervosa, that patients may have become really fascinated and interested in food, just not wanting to eat it. But and also attached to other kinds of motivational salience processes, such as perception of their own body in a slightly fearful way. That can involve a different sort of acts, different sorts of processes, still involving brain dopamine systems in in a fearful way, but sort of distorted body perception and distorted motivational significance of body perception.
Nick Jikomes 42:27
So, you know, when we think about So earlier, we talked about how, you know, the brain, it does have this innate capacity to like things in general, there are systems that mediate the linking of things and motivational systems that mediate our general ability to want to go out and work for those things. But there's also a lot of the specificity as you said, in terms of, you know, specific cues in the environment being specifically motivated by argument physiological state say, so not only do we get hungry in general, but we can become very hungry and motivated to go get something that is salty as opposed to sweet or vice versa. So how do some of these, like homeostatic systems in the brain that are tracking you know what's in deficit? And what we need more of to run our body? How do they interact with the parts of the brain that we've been discussing the dopamine motivational system and these sorts of hedonic systems,
Kent Berridge 43:21
they're very closely wired together. A lot of homeostatic systems in the brain systems of hunger and thirst, and sex and aggression and other systems are sort of associated often with hypothalamic function. Particular nuclei and particular neuron pipes in the hypothalamus. The rest of the brain circuitry is involved too. But the hypothalamus is sort of a hub before homeostatic motivations is thought, and there's heavily interact there's heavy interaction and heavy projections in going back and forth between the hypothalamus and the mesolimbic dopamine system. The hypothalamus sends neurons projections to the ventral tegmental, which is where dopamine neurons originate in the midbrain, ventral tegmental and substantial Niagra those dopamine neurons project up to nucleus accumbens and Stripe, the nucleus accumbens sends projections back to the hypothalamus. And there's other projections converting from the reward system on hypothalamus to so there's sort of massive interaction. And what this allows is for homeostatic states physiological states to cause Alia Stasia changes in pleasure, but also to cause what might be called incentive ality a seizure or motivational algo seizure, which has to change the temptation power of particular cues for say food versus drinks versus other kinds of reward. So that some become much more attractive at certain moments than others modulated by these physiological inputs.
Nick Jikomes 44:48
In terms of like, you know, in terms of the overlap between some of these things, how is it that how is it that the brain is able to achieve this sort of level of specificity? So, so if you're specifically deprived of a say, salt in your diet or some type of nutrient in your diet, somehow the brain is tracking that rather than just a general calorie deficit. And then it's motivating you to go and find something that will speak to that specific deficit. How does how to some of these hedonic and homeostatic systems link up with the sensory systems and the cognitive systems in the brain that are going to, you know, that are going to have the information about, you know, what we've learned in our environment signals something and what we should go out and be paying attention to, and these sorts of things.
Kent Berridge 45:36
Yeah. Well, that's an excellent question. And there are particular psychological rules that this system follows. The dopamine wanting system, the kind of wanting, it's producing I with my colleagues, and I call it incentive salience. And what that means is a particular kind of want, that is triggered by cues. Often in animals, it's triggered almost exclusively by cues, smell of food, desire to sight of a mate, that kind of thing. In humans, it's often triggered by cues to but we have in humans the ability to kind of imagine vividly a cue that's not physically present. So we can think about imagine foods or other things we want and vivid image we can activate the system just as well as a physical cue cam. So we have these multiple routes that turn it on, what's happening is that the obey the rules that were first described very presciently by a Canadian psychologist called delta Bindra who had an incentive theory of motivation in the 1970s. That was based upon what he called Pavlovian cues. You know, Pavlov is the scientist who said you associate a neutral cue with something like food reward, and you form an association. Now, the cue triggers their response that the third quarter which we could what Bindra said was yes, these cues are very important in triggering these incentive motivational systems to want and like particular things, but they are modulated powerfully by physiological inputs. Let's think of a couple examples. So one, you've mentioned salt and salt appetite. In our lab, we studied salt appetite. And if we were in a state of sodium deprivation like our ancestors might have been, and like deer and squirrels are and rabbits outside. What happens is a couple of hormones are secreted aldosterone and angiotensin two treated by the kidneys, adrenal glands, and this can activate brain receptors to create the salt appetite. Now ordinarily, a really salty taste like say swallowing a mouthful of seawater is a bit disgusting. If we take water from the Dead Sea, which is three times saltier than seawater, a mouthful of Dead Sea seawater is very disgusting. If we squirt a little dead sea seawater into a rat's mouth, it will show discuss the gapes and head shakes and flails just as a way to squirt it intense bitterness into its mouth. But in a state of sodium appetite, sodium depletion, when and angiotensin two and aldosterone are reaching the brain. This activates salt appetite circuitry, which activates this brain reward circuitry, including turning on opioids and dopamine in the nucleus accumbens. And in this state, even dead sea saltiness becomes positively like if we squirt it into the rats mouth. They don't respond to it with as though it were sugar rather than as though it were bitter or intense, disgusting saltiness. Now that's the that's how they Stasia that's the like. But what about wanting? Well, if we have a rat, who learns that a lever pops out of the wall, and this predicts, when it's in a normal state, it predicts a squirt of Dead Sea saltiness into his mouth. The rep soon learns to avoid that lever whenever it pops out of the wall. If we have a second lever that pops out of a different wall, and it predicts a squirt of sugar water into the rats mouth, the rat likes the sugar water. And now whenever the sugar lever pops out of the wall, the rat sort of jumps on the sugar level whenever it starts to nibble it. This is an incentive salience like thing the cue has become even though it's just about a lever, that cue has become kind of an edible, sugary like thing to the rat, and it jumps in nipples that lever. So should the rat has learned to be repulsed by the salt lever, and to jump in want this sugar lever. But now suppose the rat wakes up in a state of sodium depletion that was induced by an injection last night of hormones that turn on aldosterone angiotensin signals. So the brain now is in this sodium depletion state suddenly, for the first time in its life, it's never been in the salt appetite before we know if it tasted Dead Sea saltiness now would like it and not find it disgusting. But the question we want to ask is how will we respond to the cue? That's all that's always been repulsed by that's always predicted nasty, disgusting. This will have to relearn that the queue is now associated with a light thing. The answer is no, no no. Bindra essentially predicted this one would happen. What happens is the cue puffer the Dead Sea saltiness pops out. And today the rat jumps on that debt lever for saltiness and starts to nibble it. Just like every jump on the sugar lever, even though at this moment has not yet tasted saltiness has liked, it hasn't yet had the Dead Sea saltiness infusion into his mouth on this sodium depleted day, it instantly wants the lever that was formerly repulsive. So the cavitation value of the queue can be absolutely modulated from moment to moment.
Nick Jikomes 50:31
I see. So yeah, even though the rat has only ever experienced that lever with a dislike or disgust reaction, it has never wanted to go taste that saltiness. And it's never actually been salt deprived before that very first time that you physiologically put the animal state of salt depletion, somehow that physiological state is able to change the brain such that the animal now wants to go and interact with that lever and likes the taste of it. So somehow, you know, the sensory information about that lever, and its association with saltiness, is instead of being linked up to the aversive state networks in the brain or whatever, is suddenly hooked up to the liking networks, all in all in one shot.
Kent Berridge 51:13
Exactly. It's what I call incentive alley, a seizure where the temptation power of the cue is drastically changed, in this case, reversed from negative to positive by this new physiological state. This kind of thing is happening in people all the time too. So thinking of binge eating and neural things that connects our homeostatic hunger satiety circuits to this reward circuitry. One example that I find kind of powerful and neat is it is a neuro imaging study that was done at Cambridge University in England by team who were studying people who were born congenitally lacking leptin, they lack the gene to make leptin is what people really want to certain families in Pakistan and Turkey, and that's region of the world. They become very obese. They as children, they demand food, they constantly demand food, they're not satisfied by eating a meal and they become very, very obese. These are left and deficient people. Now, Leptin is a is a molecule that's ordinarily produced by fat cells in our body, and it acts as a satiety signal. Ordinarily, these people since they lack the leptin, they don't have the satiety signal, and it's it's understandable that they would overeat. Now an interesting thing is what happens in the neuro imaging scanner. If if hungry, ordinary people are popped into a neuroimaging scanner, and shown photographs of tempting foods, delicious foods that we would like this activates our mesolimbic system quite powerfully, if we're hungry, looking at these tempting foods, if we just have a big meal, if we eat to satiety a big meal, and then we go back into the scanner, the same foods. Looking at those photos, they don't really activate the reward system nearly as powerful anymore. So satiety has reduced our response to the food cues, we don't want those food cues. We don't want the foods. A leptin deficient person looks in the scanner, when they haven't eaten it. The food cues really powerfully activate their reward systems in the brain. Of course, if that person that leptin deficient person eats a full meal, and now goes back into the scanner, and sees the food photographs, the photographs still activate its reward system in this leptin deficient person's brain as powerfully as they did when they were hungry, you know, before the meal they've eaten. They're loaded with calories, but their brain is still hungry. And it responds to food cues with this temptation power intense wants, whether they've eaten or not, if you give an injection of leptin, artificial leptin or synthesized leptin to the person, so now this person who has never had leptin because they can't produce it, now they have exogenous leptin given to them in an injection. Now, if they eat the meal and go into the scanner, their reward system is not so activated by infusing giving them the left and now in the brain. Leptin receptors are in the hypothalamus, but leptin receptors are also in the ventral tegmental where the dopamine neurons why and there are connections from the hypothalamus to the ventral tegmental. So leptin acting on those two kinds of targets, ventral tegmental near dopamine and hypothalamus sends this modulating signal to the dopamine reward circuitry that says you don't have to be tempted by food cues at this point you're in this leptin higher, calorically seated state. But if we lack that, and the leptin deficient people give us kind of an insight into what's going on there. We see food could remain always tempting you.
Nick Jikomes 54:40
I see. So So as your physiological state changes, you go from being hungry to sated or vice versa as you become thirsty or as you become self deprived. There are literally hormones and things that change their levels change in your blood. They go into the brain and they directly change some of these neurons that in the dopamine reward system you In, in other parts of the brain that we've been talking about, and that's how some of these switches are, are actually caused the you know what, when we talked about the rat, who goes from being averse to the salt stimulus to liking it to because something, you know, it has been released into the bloodstream that's literally gone into the brain and sort of tuned to the circuits differently.
Kent Berridge 55:18
Yes, if I think of it as these chemicals are like, they're modulating the dopamine circuits, they're not sort of forcing it into a new level of activity themselves, but they modulate it. So now the system will respond differently to cues for foods versus cues for water and other things.
Nick Jikomes 55:35
How much you know, when we think about when we think about modern humans, compared to our human ancestors, you know, 1000s and 1000s of years ago, are just the animals in a natural state, you know, an animal living out in the wild, in the middle of nowhere, is almost always going to be in some kind of deprived state, right, it's always going to be sort of struggling to find enough food, there's going to be times where doesn't have enough salt, there's going to be other times where it hasn't had water in a while. And the animal is sort of always working to satisfy these deprivation states. And you know, what I want to connect that to humans is, you know, when you when you're hungry, and you eat something, the food not only tastes good, and has pleasure coming from the sensory crop qualities of the food itself. But you're sort of getting rid of a bad feeling, right? The the feeling of being hungry, is really uncomfortable, people get cranky and irritable, it's something that you want to get rid of. And so the brain is, you know, sort of coupling, these negative feelings we get when we're deprived to something with the positive feelings we get when we get the thing that gets rid of that negative sensation. But I think the sort of overall picture I have in my mind is that, you know, animals in the wild are more or less, always working to to get rid of these deprived states. And I'm wondering if that general observation in terms of that going on, and some of the brain mechanisms that underlie that, that we've been discussing, is that related to the fact that in human beings today, we live in states of basically perpetual abundance, most of us most of the time, always have more than enough food around any type of food that we want, we're, you know, I'm never going thirsty, I always have water that's available to me, all these physiological systems are never really in that deprived state, they would have been out in the wild, so to speak. And and we've got, you know, a rise in many neuropsychiatric conditions like depression. Do you think there's a connection between some of the some of the trends in in the rise of these psychiatric conditions in humans, and the fact that we're living in a state of perpetual abundance?
Kent Berridge 57:47
Well, I think the evolutionary Miss Miss match idea that you described that we evolved in situations of scarcity. And that has changed that we're wired the brain to respond as though we're always in systems have scarcity, even when we're not and lead us to overeating over consume. I think that's a real, plausible hypothesis and very widely held. How it relates to clinical depression, I'm really not qualified to say, but what I can say something about is how it relates to the nasty feelings of hunger and nasty feelings of other depravations that you mentioned. Nasty feelings of hunger, and nasty feelings of thirst and other nasty things. They were thought to be the driving force in motivation for psychology and neuroscience, from the 1930s through the 1960s, and 70s. Really, it was Dr. aversive drives hunger, thirst, sex can even be thought of as a kind of aversive drive or aggression levels that become more irritable and able to respond to provocations with aggression as an as an aversive drive. And it was thought that drive reduction that is reducing these aversive states was the essence of motivation. Neuroscience of the original neuroscience of motivation, looking at the original hypothalamic mechanisms of motivation, were absolutely sure that motivation was going to be caused by aversive dries, and that the reason you eat was to reduce that aversive drive, there was even I have a wonderful quote by Bill Miller, who was a famous neuroscientist at the time, he was recording from neurons in the hypothalamus and he thought they would go they would fire a lot when we were hungry. And he thought if we ate a meal, it would reduce the firing of these hunger neurons. So they would be an aversive feeling of hunger when we're hungry, and eating foods should reverse we lower them. And around the same time, it was being discovered that some electrodes in the hypothalamus were very rewarding. Some would rat would work to turn on 1000s of times and humans that were being implanted around the same time, in some psychiatric wards would work to turn on these electrodes hundreds of times. And Neil Miller was sure that what was must be happening, other electrodes were aversive in the hypothalamus, we don't want them turned on rats would avoid turning them on different electrodes. Neil Miller was sure that the nasty electrodes, the ones that were rats would not want to turn on him that a person would never stimulate, were neurons that were activating things like the aversive hunger drive. And he was sure that weren't neurons that reward electrodes that individual work to turn on, these were probably turning on neurons that were very different than maybe satiety neurons, neurons that could reduce the aversive drives, that's why they would be rewarding when a person would work for them. So basically, he thought, if he could record from the neuron that was avoided, that would be the hunger neuron, and he would see that neuron go down during what turned out, though, very quickly was that this was entirely opposite to the truth, what really was happening was that the reward electrodes that rats would work to turn on, these were the same electrodes that would make them eat a lot. If you turned them on freely, they would turn on a hunger apparently, the aversive electrodes that rats would never want to turn on, were the electrodes that would stop them from eating. No, it would stop them from eating when we thought by reducing the aversive hunger drive, but they didn't want this to happen. They didn't want the sweater on. So basically, it didn't make sense. That reward electrode was also essentially a hunger turning on electrode. It didn't make sense by the old Dr. theory that was drives reverse over by drive reduction theory. This was the beginning that led to people like delta Rabindra, that Canadian psychologists who had the Pavlovian incentive theory, who, whose lives began to suggest, well, maybe motivation systems in the brain aren't wired around, reducing these drives these aversive drives so much, maybe they're wired more towards the rewards themselves out in the world, and the cues that are associated with these rewards turned on. And what has happened in the intervening in the subsequent decades between 1970s and now is that it's just become very clear that yes, although hunger is aversive, severe hunger is aversive, and many other severe states are aversive. That's not the essence of their motivating properties for food, the brain is really, the hunger is modulating the reward systems response to food cues. And such, this is what's really driving eating much more than the aversive senses of hunger themselves. The debate still goes on a little bit neuroscience, but I'd say 90% of the evidence is very clear that it's incentive systems and not to drive reduction systems that are motivating, eating and other natural proceeds.
Nick Jikomes 1:02:37
And when we think about, you know, when we think about trying to use animal studies to think about humanity to think about, like addiction in humans to think about overconsumption of food and humans and things like this, to what extent does the animal research tell us something very cleanly about what's going on with humans? And where does it Where does it start to break down?
Kent Berridge 1:03:01
Well, it's always an empirical question how, what we'll transfer from animals to humans, and we find what does and what doesn't? I have to admit, you know, when we were proposing the notion that dopamine was wanting and not liking based on our right experiments, it's fair to say that nobody believed us for at least the first 10 years of that theory throughout the 1990s. In fact, I remember reading a couple times that people would say, well, the Michigan group they think dopamine is wanting but not liking but in humans, we're sure it's it's liking because it's turned on by these pleasant rewards, as indeed it is turned on its pleasant reward. It wasn't really until the early 2000s That studies in humans began to be done. That's, well, I'll give you an example. Marco Leighton, psychologists and neuroscientists up in McGill University in Montreal, would give people cocaine, pleasant drug in the hospital, he could give them cocaine, and simultaneously to giving them the cocaine which turns on dopamine systems and which they rate as pleasant and they when they take some cocaine, they find that they want to now take more cocaine. That's the thing about cocaine it Prime's the appetite for cocaine and so a person can want more at the same time that they're enjoying this first dose of cocaine. If he simultaneously suppressed their dopamine systems by giving them one of the dopamine blocking drugs, the neuroleptic antagonists that block the dopamine receptors, or if you suppress their dopamine system by original by just an hour before the cocaine giving them a an amino acid cocktail that stops their brain from synthesizing dopamine for a few hours, suppress their dopamine. Then it gave them the cocaine in this dopamine suppress state. What happened was they would rate that they liked the cane the cocaine. Absolutely. Normally even in the dopamine suppressed state, the dopamine suppression didn't change their liking for cocaine. But it did suppress their ratings of wanting to take more cocaine. So if they didn't have the dopamine suppression, they take the dose and they go Like if and they want to take more very keenly. But if their dopamine suppression, they take the dose and they'd like it, but and perfectly normally, but they didn't especially want to take more. The dopamine suppression was changing that. That kind of evidence together with evidence that Parkinson's patients who were not taking medication, so they were having low dopamine, it was thought that they had anhedonia, that they didn't find things pleasant. But if you actually ask them to rate the pleasures of things like their favorite ice cream, they gave you absolutely normal pleasure liking ratings, even though they didn't really value the ice cream or anything else at that moment. This began to accumulate this kind of evidence that in people yes, if you ask the right questions, it turns out that dopamine is mediating wanting but not mediating the like for the same rewards, just as it appeared to in rats in our lab 10 years earlier, and has continued to appear in our lab, dopamine experiments throughout the 2000s. So the human evidence began to converge Finally, with or catch up really with the rat evidence, the original psychological insight that dopamine was wanting and not liking that came from rat experiments. 10 years later, human evidence began to confirm and the the, the latest Parkinson's medication evidence that stimulating dopamine systems with a direct agonist turned on these intense wants, but not intense likes, you know, that was another piece of human evidence that conversion. So some things do translate very readily from animals to humans. I think when we're talking about the basic mechanics of these reward systems, these which are evolutionarily ancient and mammalian evolution, they transfer quite well. What will be novel and new is, of course, humans love to listen to music, we may enjoy art, you pursue all kinds of cultural pleasures and social pleasures that animals aren't going to pursue. These new things now can tap into our ancient brain reward circuitry through special human evolutionary and cultural innovations, that they are like new keys into the old locks. But the locks themselves are operating by similar principles that they always have been shared with animals.
Nick Jikomes 1:07:16
I see. So the idea would just be that in human beings where you know you not only have the the classic normal basic reward pathways and and simple addictions that can form right like you can get a human being addicted to opioids or cocaine just like you can arap. But a human being can also become addicted to ideas and symbols. And there's sort of a more of a cognitive component there, then the idea would be that, even though there's this other extra layer of learning and associations that can hook into the circuitry, it's still hooking into something that's quite conserved even between a mouse and a rat and a human being.
Kent Berridge 1:07:55
Yes, to a surprising degree, because because I have to admit that 20 years ago, I didn't think this was the case at all. 20 years ago, I thought the distinct human cognitive pleasures were entirely cortically based, and different separate from the sensory pleasures of sex and drugs and foods and things that activate the mesolimbic subcortical system. In fact, with colleagues, psychiatrist here at the University of Michigan, I collaborated in the study about 20 years ago, where we looked exactly for that. And human beings thinking that humor, funny jokes and cartoons that were humorous, would activate their cortical systems and versus looking at food cues should activate their mesolimbic reward system. And we failed to find what we were hoping to see this segregation of cognitive cortical pleasures from subcortical pleasures. The reason we failed, it turns out as other subsequent fMRI studies by others over the last 20 years have shown is that because those cognitive pleasures are actually activating the same mesolimbic system, to this surprising degree, that, that the sensory pleasures did, so things like listening to one's favorite music. In music students at McGill University of the tour and colleagues there have shown that this activates their mezzo limbic system, including dopamine release, looking at art can do the same in some individuals who really enjoy are looking at the face of a loved one can activate the same mesolimbic system, even something as abstract perhaps as sort of happiness hedonic happiness in general. Richie Davidson at the University of Wisconsin and his colleagues have done neuroimaging studies in older adults asking people to rate their their their contentment really with their lives, how satisfied they are, how happy they are with their lives. What they find is a remarkable linear relationship between the their ratings of contentment in their life and activation of the nucleus accumbens when they're in the mesolimbic. They're in the neural imaging scanner. The nucleus accumbens is the target of the subcortical dopamine systems. It's the last thing I would have expected 20 years ago to be associated with human happiness, but this is saying that possibly even that abstract happiness is related to recruiting these mesolimbic agents circuitry. That's where the evidence seems to be pointing. Now, it's not to say that cortical systems aren't also involved in all kinds of human pleasures they are, they absolutely are. That's not a surprise. What's a surprise is that the ancient subcortical systems also are and maybe possibly mediating the pleasure of those events. That's that's the surprise to me.
Nick Jikomes 1:10:28
So asking a bit more of an abstract or theoretical question. You know, when we think about emotion, and motivation, you know, why why do these emotional states exist at all? Why isn't? Why isn't everything just a chain of reflexes that can get hooked up together? You know, it seems like, you know, you could imagine that, you know, hypothetically things could be that way. And yet, they don't seem to be. So what exactly are these emotional states? And what are they doing that differentiates them or necessitates that we have them such that everything's not just a chain of of, you know, associative reflexes?
Kent Berridge 1:11:07
Right? Well, that is a wonderful question. And it is really, in a sense, the question of neuroscience and psychology is essentially the equivalent to the question of why our consciousness exists. Why do we have any awareness of things at all? Couldn't evolution have made design brains to behave appropriately in the right situations without consciousness? And many philosophers of science? And others would say, Well, yes, I would think so. So why is consciousness there? We don't have a good answer to this question. But given that consciousness is there, so we have conscious awareness of percepts, and memories and feelings, then the question is, so why have these particular kinds of emotional feelings say both liking and wanting, why are they there, in these embedded systems? And there, there's some good answers, and there's some slightly good answers is, if one could think of an ancient creature that only had say, only a wanting system or only a liking system, I would vote or to have the only the wanting assistance. Because if something wiggles that's potentially edible, and you go and jump on it and eat it, if you're a deep sea creature, ancient Indigo, that will feed you, be attracted, want it, eat it. If a pheromone for a potential mate walks over to you through the water, and you're attracted over there to meet, that will help protect perpetuate your genes. These simple wanting systems, even if you didn't, like anything, would be enough mesolimbic systems. And as I said earlier, there have been suggestions that mesolimbic dopamine systems might have evolved, not just in mammals, but much, much earlier. So that they might be shared the basic wiring diagram even in insects and crustaceans, similar to mammals. If that's the case, then ancient wanting systems did evolve long ago. Why have lightning? In addition, that has slightly good answers, we don't really have a good answer for why you would have pleasure in addition, but the answer that's been suggested that has, I think, some credibility by people like Paul rosin, University of Pennsylvania, and Tony Dickinson in Cambridge, England, is that maybe if we evolved originally wanting systems, they might have been fairly programmed for specific or innate targets, you know, the wiggly food or the pheromone, the brain would have to have wired in advance the instructions of what to want, what to respond to what to find it tempting cue, and only we'd respond to those cues. But suppose an individual could stumble upon something new, that's really beneficial, if it could stumble upon something beneficial and process that through perhaps a liking feeling or liking reaction. If that liking reaction could create could recruit the wanting circuit to target or want on this new thing, and cues associated with this new thing. You'd have a marvelously adaptive way to develop new ones based upon sort of fortuitous, happy likes, that had just happened by random on when something new is encountered, and you could improve considerably your psychological competence and your ability to thrive and pass on genes in this world. So they're suggesting the liking system is sort of a general purpose way of taking mechanisms that evolved for particular ones and giving them new targets that are adaptive to I think that's plausible. And I haven't heard a better solution. Still, one could say, Well, why do you have to feel the pleasure? And this is a question that we do not have an answer to, as far as I know.
Nick Jikomes 1:14:42
But it it does feel like an intuitive explanation to me. I guess. I guess the idea is, if I'm hearing you, right, if everything was just sort of hardwired you would have to everything would be neatly specified. Everything that you want to go out and wants to go out and get in the world needs to be hardwired. And that would really only work if an organism is living in a static, unchanging environment. But as soon as the environment becomes dynamic, and it changes as as it is for most organisms, you have to be able to learn new associations and you have to steer or or direct the attention of those motivational systems to things you've never encountered before. And so maybe the sort of effective side of this is a way to train these motivational systems when you live in a variable environment where you have to learn what to go out and get and what to avoid, because they can't be innately specified.
Kent Berridge 1:15:36
Absolutely. And the system follows the rules that Deborah Bindra the Canadian psychologist who proposed this Pavlovian theory of motivation, specified decades ago, when I say Pavlovian theory of motivation. That's what it was called, because it was cues evoking motivation. But another name that you could give it would be a flexible wanting system for developing new beneficial ones. That's exactly what it is when you pair random neutral cues, which have no motivational significance to begin with, with some beneficial event, an unconditioned stimulus, and that's emotionally dynamically arousing, liked, then those cues can become attractive too. And you'll pursue those things, even things like hunger, which, of course, is innate as a motivation. Many aspects of hunger and thirst, still interact with these learned cues, the foods that particularly attract us we've culturally learned about and even in animals, there are studies in the 1960s, kind of classic studies on little newly hatched baby chicks, little chicks. The question was, did they recognize water as something to drink right away? Or did they kind of respond to it as a glittering surface? Heck of a couple times, because it glitters and then fight? Well, that's water, you can thirsty. And the results, were suggesting that really, they kind of had to learn that the sight of water was water by Spike, this being attracted just just the glitter, then they'd pursue it, they wouldn't pursue it before
Nick Jikomes 1:17:00
having it. So even things that seem like they would likely be innate, do you often have a learn to component to
Kent Berridge 1:17:08
them? Absolutely.
Nick Jikomes 1:17:11
And what about like so so, you know, as you as we navigate our environments, and we, you know, build up this massive library of sensory and cognitive associations for things that you know, are tied to food or drink or anything else? To what extent can those learn associations and those sensory cues start to actually override the basic homeostatic system? So for example, you know, you don't have to learn to be hungry in general. That's, that's sort of baked right into the system. But you learn that all of the different cues in your environment, all the different signs for restaurants and commercials on TV, and all this stuff is associated with food. To what extent can those learned associations and those sensory representations actually become a stronger driving force than than the homeostatic part of this?
Kent Berridge 1:17:59
Well, they powerfully can. And it kind of goes back to the evolutionary mismatch theory that you described earlier, the notion that we evolved in environments of scarcity, and but now we're in an environment of abundance, and we've carried brain and psychological traits for the scarce environment to this. It is, but what is it is, is that now we are surrounded by luscious foods virtually all the time or within minutes, and you walk out the door, and they're delicious foods far more attractive than our ancestors evolved with. So we may not be particularly hungry physiologically, yet, they are attractive and might we might think, feel peckish and be willing to eat just another one or another one another. Even though we have high satiety actually physiologically within us. It's not just foods, of course, but many things can we have this ability to be tempted by queues for which we have no need to underline for our brains are or are organized to be incentive, temptation machines, and they evolve to do it very adaptively. But we are such powerful incentive temptation machines that we can be triggered into addictions, we can be triggered into over eating and obesity, and to a number of slightly maladaptive pursuits.
Nick Jikomes 1:19:21
What are what are some of the things that you guys are working on in the lab right now?
Kent Berridge 1:19:26
Well, we're always interested in the mechanisms of liking and wanting so we're still researching these hedonic hotspots and how they produce pleasure liking, we're using brain optogenetic techniques to turn them on now rather than just the drug microinjections. But what's most interesting, perhaps, that we're looking at now is looking at the wanting system and seeing how powerful it is to produce even maladaptive ones. And the example that we have came up again as kind of a surprise me lots of surprises in my career is one Counting what hurts the induction of wanting what hurts. Now, this is kind of meant to be a prototype of addictive motivation as the incentive sensitization theory of us addiction, which remember is that an addicted individual, if they're hyper reactive in your dopamine system, to drugs and drug cues, they could want it excessively, even if they don't like it. What that is to say is that liking can be detached from wanting, if you can truly become detached from wanting, is it possible then to actually come to want even what would hurt you? In addiction neuroscience today, in many animal studies in addiction neuroscience, one one criteria that's often used of as a test of is an animal like a rat addicted to a drug is whether it will be willing to incur an aversive say electric foot shock in order to get the drug. If it is, then it's going to pay that price of pain in order to get the drug that's kind of a measure of addiction. So pain is always thought of as a repulsive thing. But it is possible, what we're finding is we're, we're using optogenetic stimulation of the central nucleus of the amygdala. The amygdala is kind of famous as a sort of learning motivation interface. It's perhaps most famous for learned fears, but it also participates in learning desires. And the reason we're in the amygdala is because it helps to learn and focus the motivation on the particular thing. So we're trying to get the addictive like quality where motivation becomes very intense, very focused, and detached from liking. If we still if we pair stimulation of the central nucleus of the amygdala, which is a striatal, like part of the amygdala, like the nucleus accumbens, it has some neurobiological and psychological features similar to the nucleus accumbens, one of the psychological features is little neural stimulations in the central nucleus of amygdala can generate intense motivations, including intense once we pair if we pair. These laser stimulation of neurons in the amygdala with something nice like say a sugar pellet. In a rat who's choosing between sugar and cocaine, this rat will become a sugar addict who pursues only the sugar and ignores intravenous cocaine. If we pair this amygdala activation in a different rat, with cocaine, but not sugar, that rat will become a cocaine addict and ignore the opportunity to sugar. Normal rats in this situation, do choose both about 5050, get some cocaine, get some sugar, get some more cocaine, some more sugar, why not? They're both freely available, but we can create the addict by this pairing. Now, if we take in a third rat, the same amygdala pairing, but now we pair it with something nasty, potentially nasty, which is an electrified chakra that sticks out on the wall of the chamber just a few inches, just a little metal poking rod that sticks out of the chamber, it's a Mobile Threat does not have to touch it ever. Chambers large enough, you can entirely avoid it. But most rats out of curiosity will touch even if they have no amygdala stimulation, they'll touch once what is this, maybe twice, but the electric shock, then they'll stay back, they'll stay as far away from that rod as possible. And they'll start to kick, sand that to the chamber, they'll kick it towards the rod. It's called defensive burying. It's an anti predator behavior that rodents will show to things like scorpions or snakes on kicking sand at them to drive them away sometimes, and they'll bury the run. But if we take a rat who has the central nucleus of the mental stimulation, and we prepare it whenever the rackets within a centimeter of this rod and touches the rod, what happens is the rat gets a shock, it jumps back, it comes back and gets a second shock and jumps back. It comes in gets really interested in the rod and hovers over it eagerly and sniffs it and gets a shot perhaps on its nose and jump back comes right back to the rod and just fascinated by this rod and will get a shock after shock after shock.
If they reach 20 shots, we take them out because we don't want them to get any more socks. But God knows how high they would go. They are just attracted to this rod that hurts them. Now, they're really attracted. It's not an aggressive response. If we say to the rat, it's attracted this rod will protect you from yourself will protect you from this rod will put this big block barrier between you and the rod so you can't see it. You'd have to stand up on your hind feet to peer over the barrier if you want it and you have to jump and climb over it if you wanted to get to the rod. What is your safe just stay on the safe side. What the rat does is it climbs over jumps over and gets to the rod and touches it we grab the rat gently as soon as it touches the rod got a shot back to the safe side say okay, you're safe again. You can now stay in here it jumps from it climbs back to the run the climb over five times in a 15 minute test climb over this barrier and get shocks each time sometimes multiple sizes it seeks out and wants the rod. It also wants other cues associated with this rod that hurts it so if we perish sound every time it gets a rod shock every time it touches the rod and gets a shock it also hears the distinct sound like beep ordinary rats do not want to hear a sound that pretty Shock, they will avoid a sound that predicts shock. They don't want turn on these rats who have been attracted to the rod, if we took take them into a different situation where there's no rod, but there is a way a lever they can press to hear the shock associated sound if they want, they press the lever of many, many times to give me that shock sound again, give me the Sox I was gonna want the cues associated with this thing that hurt them. This is a very Bindra like incentive salience feature want, these are tempting cues. Now this want is for the thing that hurts and it's mediated by it's mediated, it's caused by the pairing the visual stimulation, but it's actually mediated not just by the amygdala, at the moment, the rats are attracted to that shock rod, if we look at their brains just a moment after, we find that their whole mesolimbic system is activated as they're approaching the shock rod, just as it would be if they were approaching a sugar pellet. Or if they're approaching cocaine, and equally wanted those things. They literally want the rod to Chuck's them in the same way that has that would want to reward, it's creating an addictive like motivation, focused on the rod and its cues for something that hurts them. That is sort of the proof of principle, almost stronger than I would have believed myself before we saw this, that wanting can detach so completely from liking, that it can even cause one to want, what hurts one, if it can happen for a shock, right, it can happen for addictive drugs and other addictive situations that aren't nearly as diverse as a chakra.
Nick Jikomes 1:26:33
Yeah, and I suppose that would have a lot of implications for things that we could tie this to and human beings that you know, under normal circumstances, normal ecological conditions, you're almost always going to have the wanting tied to liking in the sort of normal, intuitive way that we all experienced these things attached to each other. But in these artificial conditions where you can imagine if someone is just in a very unfortunate or unlikely natural condition, you can in fact, have the wanting tied to something aversive, something that literally hurts you. And then you continue doing that over and over again, pretty much just like you would if you were compulsively addicted to something like cocaine,
Kent Berridge 1:27:08
I totally agree. The laser in the amygdala that we use in the lab, that's sort of a sledgehammer approach to turn on this system. But a similar neural event could happen in a person, just sort of more subtle neural activations of the amygdala and mesolimbic circuitry, because of their own sort of susceptibility to inducing these neural changes and responsiveness and the 10 to 30%, who become addicted in situation, triggered by situations that make them attracted and create addictions that aren't powered by pleasure, and yet are compulsively wanted, and very narrowly focused sometimes
Nick Jikomes 1:27:45
in do you know, why the central amygdala is able to do this type of thing? Is it directly talking to some of these other systems and ways that that makes sense?
Kent Berridge 1:27:55
Well, what we know is that this, the central nucleus of the amygdala is sort of a learning motivation interface. It does learn about things that are happening in the world, and it makes them motivationally. Significant and powerful, whether it's a fear, or in this case, that desire. And it can focus the motivation, whereas Meza if we did a dopamine manipulation, we might change motivation more broadly, or just change pre existing motivations. With the amygdala stimulation, we can create the new motivation, we can control what its target is, cocaine or sugar pellet, or chakra, and we can narrowly focus the motivation on it. So it's all doing it by sort of recruiting the dopamine to one might think of, in a sense, the amygdala is here acting like a lens for the illumination that the dopamine system generates, if the dopamine system is a lamp that's generating motivation or light, the the amygdala can focus that light, narrowly like a flashlight neural beam, on pinpoint target, like and create, wanting for just that one thing. That's why we're looking at those interactions.
Nick Jikomes 1:29:04
You know, given that you study all this stuff, wanting liking how all of this stuff works, has this influenced how you like Go about your own life in terms of how you sort of train train your own brain to do things effectively?
Kent Berridge 1:29:18
Well, it's, it's, it gives a little bit of an insight. I don't think it's changed my life, but it may add a little bit of insight and knowing some of the rules by which the system operates, can sometimes be hand you know, so for example, one one rule by which the system operates is that often it's primed by the last taste or the last drink of something and if you really rather not over consumed, but you have this urge at the moment in the at the end of the meal or while you're drinking session, to continue, if you pause, if you can pause for 15 minutes or so. Often these urges will decline they are sustained. They are built up up by an interaction of the system interacting with the cues and with the reward. They can pause. So turning away from the table is, is a way, I think there was a French philosopher who wrote, If you want to maintain a reasonable body weight and not become obese, you want to step away from the table, while you're still just a little hungry. If you do that, although it's painful at that moment, because you're still a little hungry, you'd like to continue, you may find 15 minutes later, that you're not hungry, actually, after all, and The urge is gone away. The system has rules on that sort.
Nick Jikomes 1:30:35
Are there any final thoughts or things you want to reiterate? Based on everything that we discussed?
Kent Berridge 1:30:41
Well, no, I would just say that in my own personal experience and career, it's really been surprise after surprise after surprise, sometimes that involves the loss of my favorite hypotheses. Like I really did want dopamine to the pleasure liking when we started out with, it just made so much sense. There was so much evidence for it, and it was disappointing that it wasn't. But sometimes there's a silver lining, you know, and that what we learned is that the truth is almost always more interesting than our original hypotheses. Sometimes the truth is counterintuitive, and absolutely against our original hypotheses. But the truth is fascinating. And if we've follow it in this kind of follow the evidence, sometimes we learn new hypotheses, which, while surprising, may give insight.
Nick Jikomes 1:31:29
All right, well, Professor Kent Barrett, thank you for your time.
Kent Berridge 1:31:33
Thanks a lot. I enjoyed talking with you