How Dopamine Impacts Brain Function | Dr. Mark D'Esposito & Dr. Andrew Huberman
00:00:00.000 | - Let's talk about working memory.
00:00:05.140 | Some years back, but still now, you use working memory tasks and experiments in your laboratory.
00:00:10.380 | If you would be so kind as to explain what working memory is, and then I'd love to talk
00:00:15.140 | about some of the work you've done exploring the role of dopamine in working memory, because
00:00:21.680 | this is so critical to everyday life.
00:00:24.260 | And I know dopamine is a bit of a buzzword these days, but the listeners of this podcast
00:00:28.780 | anyway are pretty sophisticated in terms of knowing that dopamine is not just about reward,
00:00:34.860 | it's about motivation and goal-directed behavior.
00:00:37.980 | And I think dopamine intrigues for a good reason, that it does govern a lot of our quality
00:00:44.080 | of life.
00:00:45.080 | So what's working memory?
00:00:47.880 | - Yeah, I mean, working memory, it's interesting, I started studying it about 30 years ago,
00:00:52.280 | and I don't think I realized how important it was when I started, but what we mean by
00:00:56.060 | working memory is this ability to hold information in mind when it's no longer accessible to
00:01:00.920 | us.
00:01:01.920 | So if you tell me your telephone number and I have to put it into my phone, you know,
00:01:06.100 | it's no longer there, you just told me, but I'll hold it in my working memory until I
00:01:10.280 | can punch it into my phone.
00:01:12.980 | It doesn't have to be something that comes from the outside world.
00:01:15.120 | I could hold up, you know, I can pull up my own, if I'm filling out a form and I want
00:01:20.120 | to pull up my social security number, I can hold that in mind too until I put it down.
00:01:24.280 | So when you think about it, it's a very important, you know, ability that we have that we do
00:01:31.320 | very flawlessly.
00:01:32.920 | And what I've learned more about working memory is the working part of it.
00:01:36.800 | It's not just this passive holding information in mind, but it's being able to do things
00:01:41.840 | with the information.
00:01:43.000 | It's being able to, you know, when we do a math problem, which we don't do that much
00:01:47.980 | now that we have calculus, but if you do that in your head, you're able to sort of manipulate
00:01:51.720 | the information and do the different parts of the problem.
00:01:54.940 | Or even if you're, you know, you're trying to find someone in a crowd and you're holding
00:01:59.400 | onto some face, you're able to hold that face in mind and cross check it and search.
00:02:04.880 | And so there's operations to working memory.
00:02:07.080 | It's not just, you know, it's not just this passive maintenance.
00:02:10.720 | So when we started to think about working memory in that way, we started to realize
00:02:14.360 | how important it is for, it's, you know, I think of it as the foundation for cognition.
00:02:18.960 | Just think about reading comprehension.
00:02:21.160 | You can't understand this conversation if you can't hold in mind what's going on, you
00:02:24.960 | know, earlier in the conversation or when you're reading a book, you know, or remembering
00:02:28.440 | the sentence before it.
00:02:30.520 | So it just predicts all these abilities that allows us to read, to plan, to organize, and
00:02:38.760 | all the sort of executive functions that we're doing, right?
00:02:41.320 | We have to hold in mind rules.
00:02:42.720 | We have to hold in mind goals.
00:02:44.080 | We have to hold in mind all of these things in order to just carry out behavior.
00:02:49.960 | You know, so it's really come a long way in terms of how people are thinking about it.
00:02:54.520 | I know that Matt Walker said that, like, you know, sleep is our superpower.
00:02:59.200 | But I guess one way to sort of use this term, while we're awake, working memory is really
00:03:03.640 | our superpower because it allows us to translate, as we said, sort of our knowledge into action
00:03:08.960 | by holding this information in mind as we're thinking about what we want to do.
00:03:14.400 | If we're going to think about dopamine in the context of working memory, is dopamine
00:03:18.820 | an accelerator on working memory?
00:03:21.400 | Is it a facilitator?
00:03:22.400 | I mean, what is dopamine doing for working memory?
00:03:25.400 | And maybe we could talk a little bit about the circuitry.
00:03:28.300 | I've talked about dopamine before on this podcast, but there's a good chance that some
00:03:31.920 | of the people listening to this haven't heard those episodes.
00:03:34.080 | So maybe we could just quickly review the three major circuits for dopamine and the
00:03:38.200 | one that's relevant for working memory.
00:03:39.760 | Yeah.
00:03:40.760 | Let me start with the working memory, the circuitry for working memory, because one
00:03:43.800 | of the important things about working memory is the other type of memory is long-term memory.
00:03:50.520 | You can—working memory's short-lived.
00:03:52.520 | It's only as long as you're able to rehearse it, and then it disappears, whereas what we
00:03:56.720 | call long-term memory, if I—remembering what you had for breakfast or your vacation,
00:04:01.680 | this is information that gets consolidated and gets put into a more durable form that
00:04:06.960 | we call long-term memory.
00:04:08.200 | And the interesting thing about memory is that these are separate systems.
00:04:12.040 | Everything from working memory just doesn't pass into long-term memory.
00:04:15.320 | They're two completely different systems and two completely different parts of the brain
00:04:20.120 | that seem to control it.
00:04:22.200 | So working memory, the frontal cortex seems to be very important for working memory.
00:04:28.160 | When we are holding information in line, the neurons, the brain cells in the frontal lobes
00:04:33.360 | are active, and they stay kind of active as long as we're holding on that information.
00:04:39.120 | And they're more active when the information is relevant.
00:04:43.380 | And if we get distracted, they'll get less active.
00:04:47.160 | So the frontal lobes kind of track your—track the memory that you're holding in mind.
00:04:54.400 | Another important thing about the circuitry is that if we're holding in mind, say, digits,
00:04:59.440 | the phone number, well, that information's in your back of the brain.
00:05:03.040 | And so the frontal lobes is sort of keeping information in the back of the brain active
00:05:07.820 | because it's connected to the visual areas.
00:05:10.760 | It's able to sort of keep that information active.
00:05:13.440 | And so what we've learned is that there's not these buffers in the brain where, you
00:05:18.520 | know, if you're holding verbal information, it's in this little buffer, and if you're
00:05:21.800 | holding visual information, it's in another buffer.
00:05:23.520 | The whole brain acts as a buffer, and the frontal lobe can call up any part of the brain
00:05:28.720 | and keep that part of the brain active as it's trying to hold this information in line.
00:05:35.000 | So the mechanism for working memory is just this persistent neural activity within the
00:05:40.280 | frontal lobes.
00:05:41.480 | And so then the question is, what does dopamine do?
00:05:44.000 | Well, dopamine is one of the neuromodulators that are made in the brainstem, and it projects
00:05:49.480 | up to different parts of the brain.
00:05:51.000 | There's a system that goes up into what we call the basal ganglia, which is important
00:05:54.840 | for motor function.
00:05:56.160 | And there's another dopaminergic system that goes up to the frontal lobes.
00:05:59.760 | And what was discovered was that if you deplete dopamine, working memory drops.
00:06:06.480 | You get a significant impairment in working memory if you deplete dopamine, and if you
00:06:10.640 | replace it, then your working memory will be improved.
00:06:14.560 | And so dopamine seems to be a modulator to help this persistent activity stay persistent,
00:06:22.720 | you know, during the time that you need to keep this information in mind.
00:06:27.360 | Am I reaching too far to draw an analogy between dopamine's role in working memory, that is,
00:06:35.320 | to keep information online, and the other established role of dopamine, which is for
00:06:40.960 | movement, for the generation of smooth movement, as evidenced by conditions like Parkinson's
00:06:46.400 | where people lack dopaminergic neurons or have damage to dopaminergic neurons and have,
00:06:51.440 | you know, challenges in generating smooth movement.
00:06:54.500 | What I'm essentially asking is, can we think of dopamine as facilitating physical movement
00:07:01.200 | through one circuit, but also kind of mental movement, thought movement, and I'm thinking
00:07:08.520 | about for those just listening and not watching, I'm kind of rubbing my index and middle finger
00:07:13.440 | against my thumb, so just keeping something online, it's sort of a movement of thought
00:07:18.360 | or information, and then you kind of chuck it away and bring out the next information.
00:07:23.160 | Is that appropriate?
00:07:24.160 | - Yeah, I think that's a good way of thinking about it.
00:07:25.660 | And one might wonder, well, how can dopamine be important for memory, but also be important
00:07:29.780 | for movement?
00:07:30.780 | And it's really simple, it's just that it's acting on different circuits.
00:07:35.040 | The neurons that go to the motor areas that carry dopamine will, when dopamine is expressed
00:07:40.240 | there and boosted there, then it will be involved in movement and lack of dopamine in the basal
00:07:45.680 | ganglia will lead to neurological disorders like Parkinson's disease, that has severe
00:07:49.840 | movement difficulty.
00:07:51.760 | But when it's acting in the frontal cortex and expressed in the frontal cortex, then
00:07:56.440 | it's going to improve working memory.
00:07:57.880 | So it's just the nature of where the circuits are, where the dopamine is, that's allowing
00:08:03.960 | it to have different kinds of actions, and that's for all transmitters.
00:08:07.560 | The reason why acetylcholine seems to be more important for long-term memory is because
00:08:13.520 | it's projecting to the hippocampus, which we know is another area that's important for
00:08:17.440 | memory.
00:08:18.440 | And that's why acetylcholine doesn't boost your working memory, but dopamine does and
00:08:23.000 | vice versa.
00:08:24.640 | - So drilling a little bit more deeply into the role of dopamine in working memory, you
00:08:29.320 | did some really lovely experiments showing that if people who have low levels of dopamine
00:08:36.920 | increase their dopamine pharmacologically, I think the drug that was used was bromocriptine,
00:08:42.600 | that working memory improves.
00:08:44.360 | Conversely, if one depletes dopamine pharmacologically, working memory gets worse.
00:08:52.440 | But as I recall, there was an important baseline that is important because it really mattered
00:08:59.500 | in terms of the outcome.
00:09:00.500 | Meaning if somebody already had relatively high levels of dopamine in this circuit, increasing
00:09:05.400 | dopamine further with bromocriptine didn't impart a benefit and might've even made their
00:09:11.080 | working memory worse.
00:09:12.720 | So there's a kind of inverted U-shaped function to this.
00:09:17.320 | How does one know whether or not their baseline dopamine is low, medium, or high?
00:09:24.200 | Ergo, how do they know whether or not they would want to explore going about increasing
00:09:29.400 | dopamine through any number of different approaches?
00:09:31.640 | - Right.
00:09:32.640 | Well, most people probably have optimal dopamine, but there's a significant percentage that
00:09:37.960 | probably have too little or maybe too much.
00:09:41.440 | And unfortunately, we can't measure it in the blood.
00:09:45.440 | There isn't a blood test that I'm aware of that can measure dopamine because it's stuck
00:09:51.080 | in the brain.
00:09:52.080 | - Peripheral dopamine in the blood is not a good readout.
00:09:55.200 | - It's not a good readout, yeah.
00:09:57.440 | And especially when you're talking about dopamine in areas like prefrontal cortex.
00:10:01.800 | And so we don't have a good readout there.
00:10:04.960 | There's invasive procedures like positron emission tomography where we can inject a
00:10:08.760 | radioisotope that tags dopamine, and then we can do a scan that actually shows us how
00:10:15.880 | much dopamine.
00:10:17.280 | This scan was originally developed to show Parkinson's disease, that you can diagnose
00:10:21.920 | Parkinson's disease by showing that there's less dopamine in patients that have Parkinson's
00:10:26.240 | disease by looking at this scan.
00:10:29.360 | Obviously it's invasive.
00:10:30.360 | You're injecting a radioisotope, it's expensive, and it's not something we could all do.
00:10:34.880 | But we had used it to show that it correlates very strongly with your working memory capacity.
00:10:40.000 | So how much information you can hold online, if you can hold four or five or six letters
00:10:44.240 | when I do a span task, correlated with how much dopamine we can see in the PET scan.
00:10:49.880 | So that would be a way that we could do it.
00:10:53.560 | - So if you were to read out a string of a few numbers or letters, and I can remember
00:10:58.760 | all of those a few moments later, perhaps, perhaps my baseline dopamine levels are moderate
00:11:08.720 | in the normal range.
00:11:10.440 | Whereas if I couldn't keep that online, that might be reflective of lower baseline dopamine
00:11:16.400 | levels.
00:11:17.400 | Is that right?
00:11:18.400 | - Yeah.
00:11:19.400 | It's a very strong proxy for dopamine.
00:11:20.400 | So if your working memory capacity is seven letters, or numbers, when I say 437-1506,
00:11:27.560 | if you get that, get them all back to you pretty quickly, you probably have more baseline
00:11:32.760 | dopamine than someone who has five.
00:11:36.320 | So it's a proxy for measuring someone's dopamine.
00:11:38.840 | So that's one way to do it.
00:11:40.400 | And that's actually how we did it in our original studies.
00:11:43.680 | We actually grouped individuals based on whether their capacity, based on this behavioral measure,
00:11:50.960 | was high or low.
00:11:52.140 | And like you said, those that could only hold five or six letters, if we gave them bromocryptine,
00:11:59.140 | which was the dopaminergic agonist, we improved their working memory.
00:12:02.980 | We got them into sort of an optimal level.
00:12:05.260 | But those who were already high, we actually got them worse.
00:12:10.420 | And the moral of that story was that more is just not better.
00:12:13.780 | We're trying to get people optimal.
00:12:16.460 | And so the real question is, if we want to get people optimal, like you were inferring,
00:12:21.740 | we have to know what their dopamine is.
00:12:23.740 | Where are you on this inverted U-curve?
00:12:27.060 | Another way of doing it is through genetic studies.
00:12:31.640 | So dopamine, all neurotransmitters have to be broken down and reuptaked into the brain
00:12:39.340 | cell in order to be used again.
00:12:41.420 | And there's different ways of doing it.
00:12:42.780 | In some cells, it gets transported back into the brain cell.
00:12:46.900 | In other places, there's an enzyme that breaks it down.
00:12:50.900 | Well, there's an enzyme called COMT that breaks down dopamine in the prefrontal cortex
00:12:56.660 | specifically.
00:12:57.660 | In a large percentage of individuals, that enzyme is either overactive or underactive.
00:13:04.500 | Probably about 25% of individuals, it's overactive, and another 25%, it's underactive.
00:13:10.660 | So probably half the population.
00:13:12.340 | Now, this is going to vary, depend on where you live and where you come from and things.
00:13:19.460 | But maybe half the population either has an underactive enzyme or overactive enzyme.
00:13:24.060 | If you have an underactive enzyme, then actually more dopamine sits around and you actually
00:13:29.060 | have more dopamine than others.
00:13:30.620 | And if you have an overactive enzyme, it's the opposite.
00:13:33.620 | So we've actually shown that if you now go and genotype people with a simple saliva test
00:13:39.180 | and figure out, do they have this genetic, what we call polymorphism, where just one
00:13:43.940 | amino acid gets changed and the enzyme becomes either active or underactive, we can do the
00:13:51.940 | same thing as grouping them by their capacity.
00:13:55.060 | Those that have the low dopamine, we will make them better.
00:13:59.140 | And those who have sort of baseline high dopamine, we'll make them worse.
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