How Your Brain’s Reward Circuits Drive Your Choices | Dr. Robert Malenka

Andrew Huberman 0:00 Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Robert Malenka. Dr. Robert Malenka is a professor of psychiatry and behavioral sciences at Stanford University School of Medicine. He is both a medical doctor, an MD, and a researcher, a PhD. His laboratory is famous for having discovered some of the key components allowing neuroplasticity, that is the nervous system's ability to change in response to experience. In addition, Dr. Malenka's research is considered central to the textbook knowledge about how reward systems in the brain are organized and function. Indeed, Dr. Malenka's research over the last 10 or 15 years has merged what was once two disparate fields, the first being the study of neuroplasticity, again, the nervous system's ability to change in response to experience, and the other field being the field of dopamine as it relates to pleasure and addiction. His laboratory has shown, for instance, that when we seek out particular forms of pleasure, regardless of whether or not they are healthy for us, that changes the way that our reward circuitry works, and actually changes the way that dopamine is released and how it impacts the brain. And his work has also informed how we seek out healthy pleasures, including healthy food and social connection. Today's discussion explores all of these topics and by the end of today's discussion, you will have a rich understanding of how neurochemicals like dopamine and serotonin work in parallel to reinforce, that is, to increase the probability that we will engage in certain types of thinking and behaviors. So if you are somebody interested in neuroplasticity, that is, how the nervous system can change in response to experience, and/or you are interested in reward systems, what motivates us, and what we are likely to pursue in the future given our choices of past, and if you are interested in things like social connection, and empathy, or lack thereof, today's discussion encompasses all of those topics. It is worth mentioning that Dr. Malenka is a true luminary in all of the fields I just mentioned, as well as several other fields. In fact, when you look out on the landscape of modern neuroscience, what you'll discover is that a very large percentage of the top laboratories studying neuroplasticity and reward systems and so on all stemmed from having trained in Dr. Malenka's laboratory. So it's a real honor and pleasure to be able to host him today, and I'm sure that our discussion is going to greatly enrich the way that you think about brain function, neuroplasticity, and reward.

Andrew Huberman 2:37 Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly. ROKA understands those challenges, and the biology of the visual system such that they've designed sunglasses and eyeglasses that always allow you to see with crystal clarity. Now initially, ROKA eyeglasses and sunglasses were designed for sports performance, and as a consequence, all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty. However, the design of the glasses include some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work, et cetera, and that's how I use them. If you'd like to try ROKA eyeglasses and sunglasses, you can go to roka.com, that's R-O-K-A .com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, R-O-K-A, .com and enter the code Huberman at checkout. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods and behaviors affect your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose, or sometimes referred to as blood sugar, levels. To maintain energy and focus throughout the day, you want to keep your blood glucose steady without big spikes or dips. Using Levels, you can monitor how different types of foods, and different food combinations, as well as food timing, and things like exercise combine to impact your blood glucose levels. I started using Levels a little over a year ago and it gave me a lot of insight into how specific foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards, as well as how the spacing of exercise and my meals was impacting my overall energy. And in doing so, it really allowed me to optimize how I eat, what I eat, when I exercise, and so on, such that my blood glucose levels and energy levels are stable throughout the day. If you're interested in learning more about Levels and trying a continuous glucose monitor yourself, go to levels.link/huberman. Right now, Levels is offering an additional two free months of membership. Again, that's levels.link, L-I-N-K, /huberman to get two free months of membership. And now for my discussion with Dr. Robert

Andrew Huberman 5:21 Malenka. Dr. Malenka, Rob, welcome.

Robert Malenka 5:24 Yeah, thanks for having me.

Andrew Huberman 5:26 Delighted to have you here, both for sake of your medical knowledge and training as a psychiatrist, and of course, as a luminary in the field of neuroplasticity, dopamine and reward systems, social systems, your knowledge of autism and social interactions, a newer interest in, or perhaps old interest-

Robert Malenka 5:47 (laughs)

Andrew Huberman 5:47 ... in psychedelics and what they're doing in potential for mental health. Uh, there are just so many things that, uh, you've done in this field. I've been a long, long time fan of your work since your days as an assistant professor. I've tracked your career. I've learned a tremendous amount from you by observing you and-... from being your colleague, so really delighted to have you here.

Robert Malenka 6:07 You're making me blush and-

Andrew Huberman 6:08 Mm-hmm.

Robert Malenka 6:08 ... I don't blush easily (laughs) .

Andrew Huberman 6:10 Well, it's all, it's all, it's all true and I, and I will say-

Robert Malenka 6:13 Oh, thank you.

Andrew Huberman 6:13 ... as well, you've also trained an enormous number of incredible scientists, um, Karl Deisseroth, the Karl Deisseroth, um, Anna Lembke always speaks incredibly highly of you as a mentor and, um, somebody she's learned a tremendous amount from, and pretty much anyone that's worked on neuroplasticity-

Robert Malenka 6:30 Mm-hmm.

Andrew Huberman 6:31 ... on dopamine and reward systems, addiction, and now in the f- fields of autism and soon psychedelics as well, references you often, and you've been mentioned many times before on this podcast, if not by name, by work. So again, thank you for being here. I'd love to kick off the conversation-

Robert Malenka 6:47 Thank you.

Andrew Huberman 6:47 ... by talking about something which is very fundamental to everything we're going to talk about, but certainly fundamental to our daily lives, which is dopamine.

Robert Malenka 6:56 Mm-hmm.

Andrew Huberman 6:56 You know, we hear so much about dopamine, people talk about dopamine hits, people think about dopamine as pleasure-

Robert Malenka 7:01 Mm-hmm.

Andrew Huberman 7:01 ... dopamine reward. For the novice, how, how would you frame the dopamine system? I mean, it bu- does a bunch of different things in different areas of the brain and body, but to you, what, what does dopamine represent as its major function in the brain and could you give us a kind of general contour of the neural circuits that allow this chemical to m- more or less, um, put value on our experiences?

Robert Malenka 7:27 Yeah, that's very well put. Um, as you point out, dopamine is one of the major what we term neuromodulators in the brain, a chemical signaling messenger that the brain uses to mediate a complex array of actions. Um, its best well-known function is in what we call the brain's reward circuitry. So this is a circuit in the brain, and when we use the term circuit, what we really mean is one part of the brain communicating with another part of the brain, because the brain is this very complex, you know, the most complex organism, organ in the universe, um, with lots of different nerve cells talking to each other simultaneously. And as neuroscientists, we try to parse what different brain areas are doing and what different neuromodulators might be doing. And dopamine was discovered, oh, I should know this, many decades ago, um, and it's, it's, as I said, the major chemical messenger molecule in the so-called brain's reward circuitry. And when you're talking about... So w- what is the brain's reward circuitry? This is a part of the brain that tells us something is reinforcing in our environment, some stimuli, or in quotes, is "rewarding," makes us feel better or good, although that's a gross oversimplification. Uh, and b- before getting into the details of dopamine and its function in the reward circuitry, I think it's useful to talk about wh- why do we need a reward circuitry? Why do we need something in our brain that tells us this feels good or this feels bad? And it goes back to evolution. I, I am a biological scientist, that means I believe in evolution, um, and if you think about the evolution of our species, um, everything is driven by developing mechanisms that increase our survival and it's really useful, you need something in your nervous system that tells you some stimuli in your environment is important for your survival or some stimulus in your environment is dangerous. So it's not magic that, um, sugary, high fat laden foods are highly reinforcing and rewarding, rewarding. It's not an accident, there has to be a mechanism in the brain that tells us that. It's not an accident that most of the time, for most of us, a sexual experience is pretty reinforcing, is pretty rewarding. It's not an accident that warmth feels really good when you're cold, that water tastes much better when you're really thirsty. There has, what evolved is a mechanism to tell our s- nervous systems and tell our brains, "This feels pretty good. I should repeat the behavior that leads to that rewarding experience." And similarly, it's really important when you, you know, there is an event in your life that's highly dangerous for some s- mechanism in your brain to say, "Whoa, I don't want to go back to where that lion was," and we can get into that. So this was a long winded way of saying what the reward circuitry tells us is this e- event, this stimulus, it could be an external stimulus, like I said, a, you know, a Krispy Kreme doughnut, which I happen to love and I have to be very disciplined so I don't eat too many of them. Um, it, um, it could be a drug of abuse and maybe we'll talk about that a little bit. All of these stimuli seem to activate and cause the release of dopamine in this brain's reward circuitry.

Robert Malenka 11:31 So now we need to get into a little bit of detail. Um, neuroscientists use these very unfriendly terms (laughs) to describe different brain regions. So the home of dopamine cells, or b- brain cells are called neurons, so the home of dopamine neurons, um, are in a part of the brain, sort of what we call the lower mid-brain. Um, the dopamine neurons that are part of the reward circuitry are found in this area called the ventral tegmental area (laughs) .... which I'm sorry to have to use such technical jargon. Um, we call it the VTA. That's the acronym. And-

Andrew Huberman 12:13 I think, uh, the roof of the midbrain is the tectum, it means roof, and the base of the midbrain, it means floor, which is tegmentum.

Robert Malenka 12:22 Yeah.

Andrew Huberman 12:22 I think that's the... So there's a rationale, but it doesn't help much-

Robert Malenka 12:25 (laughs)

Andrew Huberman 12:26 ... at all to know the names, right? (laughs)

Robert Malenka 12:27 And in fact you are absolutely correct and I always forget that. (laughs) So thank you for pointing that out. Uh-

Andrew Huberman 12:32 It's a, it's a, it's a side effect of teaching neuroanatomy.

Robert Malenka 12:35 A- And then, uh, which I once did back in the early '80s, but I've forgotten everything I taught.

Andrew Huberman 12:40 It's okay.

Robert Malenka 12:41 Um, anyhow, so these dopamine neurons, and we can talk about other types of dopamine neurons, they send messages, what we call projections, um, using telegraph wires that we call axons. They send projections to many different brain regions, the key one in the brain's reward circuitry being an area, again, with a very complicated name, called the nucleus accumbens, and maybe, Andrew, you know, I actually don't know w- how that name evolved, the nucleus accumbens.

Andrew Huberman 13:13 I don't know.

Robert Malenka 13:14 And I'm sure I should know because I've been studying it for 30 years, but I have never looked up the, uh, genesis of that name.

Andrew Huberman 13:22 Well, the fortunate thing about this podcast is it's both on audio platforms-

Robert Malenka 13:26 (laughs)

Andrew Huberman 13:26 ... like Spotify and Apple, but also on YouTube, and so now we can be absolutely sure-

Robert Malenka 13:30 (laughs)

Andrew Huberman 13:31 ... that somebody has put it into the YouTube comments underneath this episode.

Robert Malenka 13:35 (laughs)

Andrew Huberman 13:35 And therefore everyone will learn, including us.

Robert Malenka 13:37 (laughs)

Andrew Huberman 13:37 So I don't know the origins of the word nucleus accumbens.

Robert Malenka 13:40 Um, and, uh, it, it's, it's a gross oversimplification, but it's the activity of these dopamine neurons in the ventral tegmental area, um, that then cause the release of this powerful neuromodulator to mo- neuromodulator dopamine in the nucleus accumbens, which has a, is part of another brain structure with a tough-to-remember name called the ventral striatum. (laughs) Um, and then magic happens. And when I say magic happens, even though we've been studying how dopamine modifies the properties of cells in this nucleus accumbens, the truth is, we don't have a deep mechanistic understanding why when dopamine is released in the nucleus accumbens, we experience that as... Uh, I'm being very cautious here. The simple way would be to say as highly rewarding, but it's a little more complicated than that. What, what it tells us is that there's something really important happening in our environment. Um, th- and-

Andrew Huberman 14:50 So di- could we say that it cues the arousal system?

Robert Malenka 14:53 It, it, it, it gets the arousal system going. There's close ties to our memory systems, which hopefully intuitively makes some sense if something really important is happening in your environment, because again, we... Uh, uh, I think what's helpful for your audience is to always be thinking about how these systems evolved from an evolutionary perspective, and if dopamine is signaling something really important and salient is happening in your environment, you want to remember that. It could be a highly rewarding experience, like a source of food. For me, it's a criti- uh, I hope... I, I like all donuts, so I don't want to-

Andrew Huberman 15:34 I do too.

Robert Malenka 15:34 ... emphasize any one manufacturer of one donut versus the other.

Andrew Huberman 15:39 That's okay.

Robert Malenka 15:39 I, I like sugar-laden, fat-laden foods. That's why I never eat them because I like them so much and I use that as an example but because that was an important event for my survival, this reward circuitry, yes, it, it stimulates my arousal system. It gets me to pay attention. Um, it also has very close ties to memory systems. Um, and to, to go off on a little bit of a tangent, I think the one... Um, I don't want to say it's a mistake. I think s- perhaps somewhat oversimplification of how people conceptualize dopamine's role in the brain is, even though it's a major important role, is for it to be active and released during highly reinforcing experiences like sex, like really good food, like drugs of abuse. It also can get activated subdivisions of this system during painful stimuli and during aversive stimuli, um, which again, are really important for you to be aware of, to say, "Oh my God, that's really bad for me." Um, and so the dopamine system, this reward circuitry and its subcomponents that maybe perhaps signal more salience or aversion, aversion in the environment are closely tied to arousal systems and memory systems. Um, again, hopefully for somewhat obvious reasons, you want to remember powerfully reinforcing events in your life as well as powerfully emotionally or physically painful events in your life. So I hope I answered, um, your question to a modest degree.

Andrew Huberman 17:26 No, um, far better than a modest degree. That, that's an excellent description of the dopamine system from a true expert. Um, and the

Andrew Huberman 17:34 question I have is about some of the context and nuance of the system, but in, in sort of real world terms, how, how should I think about this? Even in my training as a neuroscientist, I know neurons can be-

Robert Malenka 17:47 Mm-hmm.

Andrew Huberman 17:47 ... a little active, a lot active, everything in between. They can be active over long periods of time or-

Robert Malenka 17:51 Yeah, yeah.

Andrew Huberman 17:51 ... short periods of time. But l- let's use the example of the donut. I'm, I'm, I like a glazed old-fashioned donut.

Robert Malenka 17:57 (laughs)

Andrew Huberman 17:58 I actually don't have a craving for sweet things-

Robert Malenka 17:59 (laughs)

Andrew Huberman 18:00 ... but donuts is, is, is an exception. I like the glazed old-fashioned donut.

Robert Malenka 18:04 Ah.

Andrew Huberman 18:04 But if I were to see just a little piece of a glazed old-fashioned-

Robert Malenka 18:08 Yeah, yeah.

Andrew Huberman 18:08 ... donut versus a full glazed old-fashioned donut...... could I expect that more dopamine is released to the anticipation of the complete doughnut?

Robert Malenka 18:19 (laughs)

Andrew Huberman 18:19 And then the other question is-

Robert Malenka 18:20 Yeah, yeah.

Andrew Huberman 18:20 ... how does context influence the dopamine system? For instance, if I'm very full-

Robert Malenka 18:25 Yup.

Andrew Huberman 18:26 ... a glazed old-fashioned doughnut might be aversive to me.

Robert Malenka 18:28 Yeah.

Andrew Huberman 18:29 Um, whereas if I'm just a little bit hungry, um, or if I'm actually more, uh, on a schedule of rewarding myself or abstaining from-

Robert Malenka 18:36 Mm-hmm.

Andrew Huberman 18:37 ... sweet, fatty foods, then abstaining from the food might be its own form of reward.

Robert Malenka 18:42 Yeah. I mean-

Andrew Huberman 18:43 And so to me, the dopamine system seems incredibly simple and yet incredibly prone to immediate context and the kinds of nuance that, uh, I mean, we're constantly juggling. I'll interrupt myself to say that we're constantly juggling a bunch of different reward contingencies. We want to, um, you know, have good health metrics and maybe have a certain aesthetic qualities to our body, but we also want the doughnut. And so how does a simp-

Robert Malenka 19:07 (laughs)

Andrew Huberman 19:07 ... a system as simple as a one neuromodulator system in the VTA to nucleus accumbens-

Robert Malenka 19:12 Yeah.

Andrew Huberman 19:13 ... and with some connections to the memory area, s- how does it balance all of that information in real time? To me, that's just, like, staggeringly complex, but also incredibly interesting.

Robert Malenka 19:24 Um, I, I think you, uh, beautifully put, beauti- very eloquent description. Um, you just said it, it's staggeringly simple, simultaneously staggeringly complex. And y- you asked several different questions. So context makes an enormous importance, and that's one of the reasons I became interested in the dopamine reward circuitry, is, as you know, as a colleague in the ner- academic neuroscience world, but your l- listeners probably don't, I started out my career studying very basic mechanisms of plasticity. How does the brain modify itself? And what makes the brain different than compute, the comp- computer hardware is our, the physical connections in the brain are constantly changing, the strength of the communication. Similarly for the dopamine reward circuitry, it's highly plastic and it's highly contextually dependent. Um, and so you gave the example of doughnuts and feeding, and I'll answer your question about the cues. Um, yes, it's, I used to give the example of Thanksgiving, so let me give that example. You know, the morning of Thanksgiving, all, for most of us, in a, in the United States, um, the morning of Thanksgiving, if you're at home visiting your parents, the smells of the apple pie, the smells of the turkey cooking are highly appetitive, highly reinforcing. You're anticipating that fun event. You're anticipating Uncle Joe coming to visit you for Thanksgiving. And that's all because these cues, the smells, the anticipation of Uncle Joe's, your previous experiences, are part, are part of your memory system sort of talking to, in a simple way, your reward circuitry. So you're building up this anticipation. One could almost say this craving, which maybe we'll talk about in the context of addiction, and then, uh, make a long story short, think about that evening at the end of Thanksgiving, those exact same cues, the exact same smell of the apple pie, turkey, and Uncle Joe himself. At the very least, they're no longer appetitive, meaning they might actually be aversive. The last thing you want is a piece of apple pie. You can't wait for Uncle Joe to leave your Thanksgiving dinner. And I always argue that does not happen magically. That happens because your brain has been modified by the context in which it sits, and this very important modulatory system, this reward circuitry is responding to the exact same stimuli with a very different response. So that, I'm just telling you, I'm repeating what you said, the phenomenology and, and again, my other favorite example is any of us who have been in an intimate relationship knows that the, the love of your life can turn to the bane of your existence in 20 seconds. Um, and again, that doesn't happen magically. This person who you crave, who you love does something, and two minutes later, your brain is saying, "Oh my God, I, you know, I may have to break up with this person," or, "This is an incredibly painful experi- emotional experience." And what fascinates me about the brain is how does the brain mediate that rapid change? So now back to, so yes, context makes, is everything about how this powerful neuromodulatory system that uses dopamine works, and the truth is, we don't know. It's because the inputs onto these dopamine neurons, the other nerve cells that are driving the activity of the dopamine neurons, and I- I've actually studied this in my lab at Stanford University with a colleague you know well, Liqun Luo, who's a, uh, uh, you know, a world-class neuroscientist, um, we've studied the complexity of the neuroanatomy of the dopamine system. And these dopamine neurons in the ventral tegmental area, the s- the- the source of the reward circuitry dopamine are receiving inputs from all over the brain. They're receiving, you know, indirectly or directly inputs from visual areas, from somatosensory areas. Um, a- and I'm not giving you a really good answer because that's one of the goals of my research to try to understand how context, how the history that you've had with these cues, which we're gonna get back to, of the doughnut or of a drug, how has that modified how this neuromodulatory system responds? Um, similarly, the- the nucleus accumbens, the- the target of this powerful modulator dopamine is receiving-... communications, what we call inputs from all sorts of brain regions that you know about, Andrew, your audience may not. They, it receives inputs from an area called the hippocampus, which you may have covered in previous podcasts, which is very powerfully, very important for memories, both establishing new memories... And again, remember, that makes sense. You want this system, this dopamine reward circuitry to be very connected to memory systems. So the, the nucleus accumbens, the activity in the nucleus accumbens is modulated by dopamine while it is receiving information from the hippocampus, which helps encode new memories, while it's receiving information from a brain area called the amygdala, which tells, i- is a part of the brain involved in our emotional experiences. The accumbens also receives inputs from the prefrontal cortex, which is this brain area, as you know better than me, (laughs) Andrew, um, is important for decision-making, for planning our activity and I could go on and

Robert Malenka 25:38 on. Um...

Andrew Huberman 25:38 Well, can we talk about prefrontal cortex-

Robert Malenka 25:40 Yeah.

Andrew Huberman 25:40 ... for a moment? Um, because, um, it always was surprising to me that prefrontal cortex is talked about as this higher executive function area. But then when you look at the neuroanatomy-

Robert Malenka 25:54 Mm-hmm.

Andrew Huberman 25:55 ... it's, as we say monosynaptically, as y- you and I know, w- one connection, um, away from structures like the amygdala, one connection-

Robert Malenka 26:03 Mm-hmm.

Andrew Huberman 26:03 ... away from structures like the, the nucleus accumbens. In other words, prefrontal cortex to me is every bit as ancient, um, as some of these other structures that we think of as more ancient. And really the whole ancient evolves then gets a little bit dicey because-

Robert Malenka 26:17 Yeah.

Andrew Huberman 26:17 ... certain areas are, like the prefrontal cortex, are more elaborated in humans but, but to me the prefrontal cortex seems to be especially important in the context of this thing of scaling the reward response or context of the reward response because it can set rules. It- it seems to know, um, okay, we're recording a podcast now and there are certain rules or certain things that we're going to do-

Robert Malenka 26:41 (laughs)

Andrew Huberman 26:41 ... and not do.

Robert Malenka 26:42 Yeah.

Andrew Huberman 26:43 Um, but what's fascinating about the... And I'm so glad you gave a bunch of different examples because what's fascinating, for instance, about the, uh, the relationship example is that, yes, at one moment, um, we can adore somebody and another moment later they do something or don't do something.

Robert Malenka 26:59 (laughs)

Andrew Huberman 26:59 We can be incredibly frustrated with them. They can even become aversive to us.

Robert Malenka 27:03 Yeah.

Andrew Huberman 27:03 Um, hopefully that doesn't happen too frequently.

Robert Malenka 27:05 Hopefully.

Andrew Huberman 27:05 But, um, I think we've all had the experience of a donut, an event, or a person actually looking different to us-

Robert Malenka 27:16 Mm-hmm.

Andrew Huberman 27:17 ... in a, you know, from one moment to the next, hopefully not at random, right? And so to me it seems like, um, the prefrontal cortex is uniquely positioned to really say, okay, right now we are in a mode of, for lack of a better word, love and loving. Like being the, in the verb-

Robert Malenka 27:33 Mm-hmm.

Andrew Huberman 27:33 ... tense of loving or be in the verb tense of arguing. We're now arguing.

Robert Malenka 27:37 Yeah.

Andrew Huberman 27:37 We know, we're in the verb tense of, of, of reconciliation.

Robert Malenka 27:40 Mm-hmm.

Andrew Huberman 27:41 You know, kind of somewhere in between or something of that sort. And how a structure in a circuit as s- simple as the dopamine system, right, one molecule-

Robert Malenka 27:50 Yeah.

Andrew Huberman 27:51 ... could suddenly say, oh, you know what? Now getting over my anger is rewarding. Whereas five minutes ago being right and being the most angry was rewarding and then five minutes before that, again we're accelerating this movie, but five minutes or five days or five years before that, this person could do no wrong.

Robert Malenka 28:07 Yep.

Andrew Huberman 28:07 And the dopamine system is just cranking out dopamine-

Robert Malenka 28:10 (laughs)

Andrew Huberman 28:10 ... saying whatever you do I'm just delighted by it.

Robert Malenka 28:13 Yeah.

Andrew Huberman 28:13 Incredible.

Robert Malenka 28:14 Yes.

Andrew Huberman 28:14 Like to me, I can't think of a more interesting system in neuroscience.

Robert Malenka 28:17 Well-

Andrew Huberman 28:18 Yeah.

Robert Malenka 28:18 I mean that was eloquently put. Um, I agree with pretty much everything you said. I don't have much to add because what you're pointing out is w- the challenges of studying these systems, the importance of studying these systems and the challenge of presenting how the brain works to this podcast audience. Because on the one hand you have done a mar- a fantastic job over the last few years in your podcasts of making complex, um, subjects accessible to a lay audience.

Andrew Huberman 28:59 Thank you.

Robert Malenka 28:59 Um, and get them to be thinking about how our modern view of how the brain works may, could be used to enhance health, could enhance mental wellbeing. But as neuroscientists, academic neuroscientists ourselves, we, we know you know you are oversimplifying things, and the actual functioning of a system like the dopamine reward circuitry as you just eloquently point out is so much more complex. Um, it's modified by these prefrontal, um, inputs which are simultaneously telling our memory systems, you know, pay attention here. Um, I- I'm repeating what you just said. The context makes a big difference. The history you have with the person or stimuli with whom you're interacting. Like, to bring this back to your in- you know, which I never... If the initial question is a small piece of a donut activate, the cue that that small piece of a donut activate the reward circuitry and cause release of dopamine to the same extent as the full donut, depends on your experience with donuts. (laughs)

Andrew Huberman 30:16 Mm-hmm. Mm-hmm.

Robert Malenka 30:16 I mean, I think for you and me because we seem to both ha- you know, like donuts, they're highly appetitive for us, um, probably doesn't matter because we have learned even a little piece of a donut, it-... activates all of our memory systems saying, "Man, that's an old-fashioned glazed donut. I want to eat that," or, "I want to get one," or, "I want to have the discipline not to eat it." Um, so I hope I'm answering your question. It's, and I'm, I'm shifting topics completely, but that's why addiction is so challenging, because-

Andrew Huberman 30:48 Well, let's talk about that.

Robert Malenka 30:49 ... um...

Andrew Huberman 30:50 Let's talk about that because you've done a, a ton of important work in this area of addiction. I mean, one of the basic questions I have about addiction is, you know, we hear that certain drugs are more addicting than other drugs or certain behaviors.

Robert Malenka 31:02 Mm-hmm.

Andrew Huberman 31:02 We also hear that e- that we can become addicted to anything.

Robert Malenka 31:04 Yeah.

Andrew Huberman 31:04 When Anna Lembke was on this podcast, um, I said, "What's the most, um, unusual addiction you've ever seen?" And she talked about a patient, um, who sadly, um, committed suicide at some point later that she told us had been addicted to water-

Robert Malenka 31:18 Mm-hmm.

Andrew Huberman 31:18 ... to drinking of any kind. First alcohol, but then water eventually.

Robert Malenka 31:22 Yeah.

Andrew Huberman 31:22 Um, and so, a- so my question about addiction in the dopamine system is, you know, for, let's pick a drug, um, like cocaine.

Robert Malenka 31:30 Mm-hmm.

Andrew Huberman 31:31 Um, I've never done cocaine.

Robert Malenka 31:33 Mm-hmm.

Andrew Huberman 31:33 Um, but people who have done cocaine tell me that it feels very good, um, and one of the more salient features of the cocaine high is that it comes on very fast and it ends pretty quickly too.

Robert Malenka 31:47 Mm-hmm.

Andrew Huberman 31:47 Is the rate of dopamine increase related to the addictive property, uh, of a drug or behavior, um, as much as how much dopamine is released?

Robert Malenka 31:59 And that's a very sophisticated question and the answer is yes. And that's usually the, (laughs) uh, the lecture I give. The way I think about addiction, um, and obviously my friend and colleague Anna Lembke is one of the world's experts in terms of the understanding the human experience of addiction. I have studied it as a cellular molecular neuroscientist trying to understand how addictive substances modify reward circuitry, modify the connections in the reward circuitry, modify how dopamine neurons act. And the way I, you know, like any what appears to be s- a simple term, it's layered with complexity, um, addiction is somewhat of a continuum. And I like to think about whether you're talking about substances like cocaine, and I will a- explicitly answer your question soon, or opioids as we, as you know we're going, in this country there is an opioid epidemic, um, I, I, I do like to think about addictive liability.

Andrew Huberman 33:06 Mm.

Robert Malenka 33:06 And it is th- in my view it is pretty clear that when we're talking about drugs they have different degrees of addictive liability. I mean, I had a cup of coffee this morning. Am I a... And many of us l- listening to this podcast, it's really hard to start our day without getting that hit of caffeine. But are we addicted to caffeine? That's a tricky question because I've never heard of anybody robbing a bank to get caffeine, d- destroying their personal life to get caffeine. Um, so I would say caffeine causes tolerance but I would not say it has a particularly high addictive liability whereas drugs like psychostimulants like cocaine, um, have a very, or opioids, have a very high addictive liability. So to answer your mechanistic question, there have been some famous studies done, um, by the director of the National Institute on Drug Abuse, Nora Volkow. Um, simultaneously there have been studies in animal models of addiction where y- you nailed it. The, in a rough way, the addictive liability of a substance is directly correlated with two aspects of dopamine. How much dopamine is released in the accumbens and the kinetics of the dopamine release as you said. How rapidly it's released. To get a little technical, even with a drug like cocaine or opioids, it's not only the drug itself, it's the route of administration because the route of administration influences the kinetics, meaning how fast that drugs gets into your brain influences the reward circuitry and how fast it causes a big rapid release of dopamine. And some of your podcast listeners may be old enough to remember the crack cocaine epidemic or freebase cocaine. And cocaine does have, like methamphetamine, a very high addictive liability. I teach the neurobio- I, I give lectures to students at Stanford about neurobiology of addiction as part of a team course, team taught course. I have kids, um, who I had to deal with and what, you know, what I s- always say is, you know, you, it's not that if you use this drug you're automatically going to become an addict, um, but you're taking that risk and it is impossible to become addicted to a substance if you've never used it by definition, but back to the route of administration. So I, I went off on a tangent there.

Andrew Huberman 35:50 Well, that's actually an interesting statement-

Robert Malenka 35:52 Yeah.

Andrew Huberman 35:52 ... um, you know, because I think we may have heard that in high school though I, um, to be honest, wasn't the most attentive-

Robert Malenka 35:58 (laughs)

Andrew Huberman 35:58 ... high school student and I regret that. High school students pay attention.

Robert Malenka 36:01 You did okay for yourself (laughs) .

Andrew Huberman 36:02 I, eventually I came around but, but it, it was an uphill battle there.

Robert Malenka 36:05 (laughs)

Andrew Huberman 36:06 Um, but you, that you can't become addicted to something that you've never done which, um, I just want to earmark that because I think it's a profound statement because it points to the importance of the memory system but also plasticity.

Robert Malenka 36:20 Yep, absolutely.

Andrew Huberman 36:20 And so I, I want to make sure that eventually we get around to talking about how, um, the amount of dopamine released and the kinetics, how that might influence plasticity.

Robert Malenka 36:28 Absolutely.

Andrew Huberman 36:28 Basically what I'm asking here or queuing up in the back of your mind is...... whether or not addiction is just related to the sensation that we have when we indulge in a behavior, or when we are under the influence of a drug, or whether or not it actually modifies neural circuitry in a way that, um, makes a broader range of, uh, drugs or experiences attractive to us.

Robert Malenka 36:56 It's probably the latter, but so let me get back and I will answer that in a second, to the point I was making. So it's not only the substance, it's the route of administration. So, and I, you know, as I said, you can't develop a problem w- with a substance and develop a s- substance abuse problem if you never take it. But snorting cocaine is a different experience than smoking it or injecting it. And one of the reasons the crack cocaine, um, epidemic was so powerful is it, uh, it gets into when you're smoking it or injecting it, it gets in, and the, and people do this now with methamphetamine. I mean, meth addicts, most of them, and that is another epidemic i- in our country, most of them smoke it. And that, the danger of that is the drug, whether it's cocaine, methamphetamine, gets into your brain almost instantaneously, causes a very rapid, powerful surge of dopamine in the accumbens, in this reward circuitry. And that, the feeling you get, which... And we're going to get into this, is not necessarily a happy feeling.

Andrew Huberman 38:10 Mm-hmm.

Robert Malenka 38:11 And it only lasts... It can last for t- t- tens of seconds or a few minutes, and it's a feeling that for, g- gives you this overwhelming compulsion and urge I want to do it again.

Andrew Huberman 38:29 So, yeah.

Robert Malenka 38:29 Even though it may not actually-

Andrew Huberman 38:32 (laughs)

Robert Malenka 38:32 ... feel all that good. It's, it's, it's a real... And, and again, this gets into, you know, we didn't have an addiction problem for any substance other than alcohol, um, you know, th- for most of humanity's existence because these substances like cocaine, methamphetamine, synthetic opioids like fentanyl, they didn't exist. And our brain, you know, the truth is our brains are, were not, are not designed to handle those kinds of very powerful substances.

Andrew Huberman 39:08 As many of you know, I've been taking AG1 daily since 2012, so I'm delighted that they're sponsoring the podcast. AG1 is a vitamin mineral probiotic drink that's designed to meet all of your foundational nutrition needs. Now, of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every day, but oftentimes, I simply can't get enough servings. But with AG1, I'm sure to get enough vitamins and minerals and the probiotics that I need, and it also contains adaptogens to help buffer stress. Simply put, I always feel better when I take AG1. I have more focus and energy and I sleep better, and it also happens to taste great. For all these reasons, whenever I'm asked, "If you could take just one supplement, what would it be," I answer AG1. If you'd like to try AG1, go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs plus a year supply of vitamin D3 K2. Again, that's drinkag1.com/huberman.

Robert Malenka 40:04 So where do you want to go from here? You asked a question about, you know, the, the neural mechanisms of the, of what we call addiction.

Andrew Huberman 40:12 Yeah, I'd like to know about the role of neuroplasticity in addiction.

Robert Malenka 40:15 Yeah.

Andrew Huberman 40:15 I, I do want to highlight something you said, and I apologize for, um, interrupting a, a moment ago-

Robert Malenka 40:20 No, absolutely. (laughs)

Andrew Huberman 40:20 ... and then, and then I refrained, but it was an interruption based on real excitement because a, a, um, uh, a person I know quite well who is a recovered cocaine addict-

Robert Malenka 40:30 Mm-hmm.

Andrew Huberman 40:30 ... told me, and that by the way, folks, this isn't I have a friend and I'm actually, you know... I truly have never tried cocaine.

Robert Malenka 40:36 Mm-hmm.

Andrew Huberman 40:36 Um, and this person said that the first time they did cocaine, his thought was, "I hate this and I can't wait to do it again."

Robert Malenka 40:46 Ex- And, uh-

Andrew Huberman 40:47 And that's exactly how you described it.

Robert Malenka 40:49 And I think that is a fairly common experience with people suffering from an addiction disorder. We're not supposed to use the word addicts anymore because that's a little bit judgmental, um-

Andrew Huberman 41:04 Oh, is that the, that's the new nomenclature?

Robert Malenka 41:06 Uh, something along those lines.

Andrew Huberman 41:07 Got it. Oh, calling someone an addict-

Robert Malenka 41:09 Onalinkini, you know-

Andrew Huberman 41:09 ... as opposed to being addicted.

Robert Malenka 41:11 Yeah, being, um-

Andrew Huberman 41:11 Got it.

Robert Malenka 41:12 And, um, uh, uh, that is a beautiful description. I hate it, but I want to do it again. Um-

Andrew Huberman 41:19 Amazing.

Robert Malenka 41:19 ... and again, it just shows the pow- the power of this system, which remember evolved for our survival. So a very simple way of thinking about it is these drugs are tricking the reward circuitry to say, "This stimulus, this experience is really important for my survival. I have to go do it again and again." And, uh, a- again, a side question is, the huge question is, why does some people develop an addiction problem and others who have used this substance j- just don't? Um, and as, again, as a world-class neuroscientist yourself, you know the answer. It's always a complex combination of underlying genetics, the environment in which they find themselves, the environment in which they grew up, and how that modified their reward circuitry. So to get at your question, um, one set of experiments my lab did, which other labs did too, I don't deserve the sole credit for this, is showing that drugs of abuse cause powerful plasticity in th- the neurons that make up the cells that make up the reward circuitry. And in fact, drugs of abuse like cocaine, methamphetamine, opioids like morphine, heroin...... change the, what, the synapses. The synapses are the connections from other nerve cells onto dopamine neurons, onto the nerve cells in the accumbens. And these connections, these synapses can change, and drugs of abuse cause powerful changes in those connections and therefore powerful changes in the activity of the dopamine neurons and the neurons in the, in the ventral, in the, in the nucleus accumbens. And in fact, the types of changes that occur appear to be similar to the types of changes that have evolved for good uses, for adaptive forms of learning and memory. Um, so again, this is an example that this epi- superf- superficially simple dopamine reward circuitry is changing all the time. It is highly plastic and can become more sensitive to certain experiences, you know, et cetera, et cetera.

Andrew Huberman 43:48 Well, could I ask a question about some of the general contours of the plasticity-

Robert Malenka 43:52 Mm-hmm.

Andrew Huberman 43:52 ... and the dopamine system?

Robert Malenka 43:53 Mm-hmm.

Andrew Huberman 43:53 Um, you said before, and, and I love this statement even though-

Robert Malenka 43:57 (laughs)

Andrew Huberman 43:57 ... it's very simple, but in its simplicity, it's really elegant that we can't become addicted to s- a substance or a behavior that we haven't, um, taken or-

Robert Malenka 44:05 Mm-hmm.

Andrew Huberman 44:05 ... partaken in. So is there data to support the idea that just one exposure to cocaine or one exposure to some sort of behavior can lead to a lasting change in the dopamine system such that one's propensity to be addicted to that substance again if one were to indulge in the future or behavior again in the future is increased? And I have a very particular reason for asking this, but I'm very curious what the answer is.

Robert Malenka 44:38 I mean, (laughs) in, in the work my lab and other labs have done in preclinical rodent models, (laughs) I want to, um, the answer is yes. A single administration of a drug of abuse like cocaine, like e- eh, morphine can cause relatively several days, several weeks ch- of changes in the connections onto dopamine neurons and onto, um, the neurons in the nucleus accumbens. Those changes, that does not mean these changes are permanent, uh, or, um, or irreversible, but the changes last a long time. Um, and again, the big question for understanding the neurobiology of addiction is w- you know, those changes are probably happening in most people who take the drug in this case. And we can talk about other stimuli-

Andrew Huberman 45:36 Mm-hmm.

Robert Malenka 45:36 ... non-drug stimuli that can become in quotes, "addictive." You know, again, why in certain individuals, to be honest, it's, it's not a big deal. Yeah, I did cocaine at this party. It was nice, but I don't feel any craving or urge to do it again. Um, whereas other individuals, it sets them down, you know, a, a very bad path and really badly affects their life. And that's a huge question in the research field, because obviously if we could make predictions on which individuals are more susceptible, um, and, you know, not to get too political here, um, but eh, eh, it's also, you know, whether you become ha- eh, develop a problem with addiction or not is influenced by the other parts of your life. Do you have other ways of getting reinforcing stimuli, getting satisfaction, s- having an outlet, that other ways of activating your reward or dopamine circuitry-

Andrew Huberman 46:39 Healthy ways.

Robert Malenka 46:40 ... or you know, healthy ways.

Andrew Huberman 46:41 Right.

Robert Malenka 46:41 Like, you know, as you have articulated I think in, in your podcast, getting exercise, you know, you and I both like to get exercise. I feel really good. Sometimes it's painful during the exercise, but afterwards I feel great. Um-

Andrew Huberman 46:57 Very, almost the inverse of, of the cocaine response.

Robert Malenka 46:59 Yeah. Um, yeah. Um-

Andrew Huberman 47:01 The desire and then the I hate this but I can't wait to do it again, it seems like exercise is often the opposite.

Robert Malenka 47:06 (laughs)

Andrew Huberman 47:07 It's I hate this, I don't want to do this. And then at, afterwards, gosh, I always feel better-

Robert Malenka 47:11 (laughs)

Andrew Huberman 47:11 ... and I'd be happy to do it again.

Robert Malenka 47:12 Yeah. I mean, y- yes. I mean, I like to exercise chasing a ball. That, because that gets me off thinking about this hurts. (laughs) But, um, so anyhow, back to addiction. Um, so yes, these drugs can cause... Yeah, I don't want to S- definitely not permanent changes from a single exposure, um, you know, and, and the types of studies I'm talking about were all done in, you know, experimental animals. So h- how that relates to what happens in e- our brains, in human subjects' brains is, you know, is not completely clear. But I think there are parallels. So the changes might last, you know, a few days, a week or two. Um, but one can see if somebody... There have been studies done where, in an animal model, if you give repeated administration of a drug like cocaine, the changes get stronger and they last longer, which is kind of intuitively obvious. Um, but again, the big question is why, um, in human subjects there are people who can use these substances and not develop a serious problem, and there are others where they're, they're very, very damaging. Um, and you know, and then that's why I still make the point, if you're a young person, if you, you're, do you want to take that risk? Is it worth it, um, to have that experience? And that's an individual decision.

Andrew Huberman 48:44 Mm-hmm.

Robert Malenka 48:44 Um...

Andrew Huberman 48:45 W- we've cut, we've done some podcast episodes about alcohol, cannabis-

Robert Malenka 48:47 Yeah.

Andrew Huberman 48:47 ... et cetera, and there does seem to be a pretty wide variation in people's response to the information.

Robert Malenka 48:52 Absolutely.

Andrew Huberman 48:52 I think because there are people out there who... Well, I've, I've got friends who are recovered alcoholics-

Robert Malenka 48:57 As do I.

Andrew Huberman 48:58 ... who, who will tell me the first drink they took-

Robert Malenka 49:01 Yep.

Andrew Huberman 49:01 ... they use language like...... you know, the, it combined with the, um, chemistry of my body in a way that nothing before ever had, and they felt like it was like this magic elixir, right? That has not been my experience with alcohol.

Robert Malenka 49:16 And I, and I-

Andrew Huberman 49:18 And-

Robert Malenka 49:18 ... I've heard the same stories and it's, it's hard for me to relate because like you, alcohol does not have that effect on me.

Andrew Huberman 49:26 Mm-hmm.

Robert Malenka 49:26 And that's where that's, it's hard to believe that kind of immediate response to alcohol is due to their env- the environments in which they grew up, although that can have an influence.

Andrew Huberman 49:39 Mm-hmm.

Robert Malenka 49:39 That just feels almost more genetically encoded. And there is evidence that issues with the use of alcohol and developing alcohol use disorder does run in families. Um, and obviously if it runs in family, you have to worry about how the environment of that family influences it. But there's a lot of studies saying there is a genetic component. Um, maybe like you, if I have a drink or two in the afternoon, I just fall asleep.

Andrew Huberman 50:06 Yeah, I-

Robert Malenka 50:06 And it does not have that effect on me.

Andrew Huberman 50:09 Mm-hmm. No, yeah, no.

Robert Malenka 50:10 And, um, and, and one could imagine similar things for other drugs of abuse. There are people who have used cocaine, have used methamphetamine who, you know, who find it modestly enjoyable, but it's not, uh, you know, the be all or end all. It isn't this incredibly powerful experience. And you just talked about, I think a, a friend or a colleague who said, "I hate it. I hate that, but I want to do it again." And that's fascinating.

Andrew Huberman 50:39 Yeah, they're now a recovered, uh, alcoholic and cocaine addict.

Robert Malenka 50:42 Yeah.

Andrew Huberman 50:42 And they've s- they've abstained for many years, but still get a little bit of a gleam in their eye when they talk about alcohol or cocaine in a way that I just can't relate to.

Andrew Huberman 50:51 Um, you know-

Robert Malenka 50:51 I can relate. I mean, can I tell you a little vignette about me, which I love to tell? (laughs)

Andrew Huberman 50:56 Sure, sure.

Robert Malenka 50:56 Um, and it gets into how the reward circuitry is so closely associated with m- memory systems and how cues associated with powerful experiences develop their own reinforcing or aversive quality. So long story short, when I was a young kid, in, I can't remember, in my 20s, maybe 20, I spent a few weeks in Paris. I started smoking cigarettes. I mean, this is a long time ago. And I got, it's, cigarettes are very interesting. Nicotine is highly addictive as are, as the tobacco companies were fully aware of.

Andrew Huberman 51:37 High addictive liability?

Robert Malenka 51:38 Very high addictive liability.

Andrew Huberman 51:40 People will rob people for the money to buy cigarettes?

Robert Malenka 51:42 Um, they may not rob because, although they're, uh, b- my understanding is they've become quite expensive, but-

Andrew Huberman 51:53 I guess they'll devote significant income.

Robert Malenka 51:54 Count- counterfeit cigarettes are a huge market for organized crime. There are thir- parts of our, of our, in the world, third world countries where organized crime produce counterfeit cigarettes and are making hundreds of millions or billions of dollars. Um, and s- so I, I think nicotine as it is delivered in cigarettes, as you know, I mean, tobacco companies put in a lot of work to figure out the exact dose of nicotine that will make you get that kind of feeling that only lasts for a few minutes, so you want to do it again and again. Um, so, uh, we can talk about the... And nicotine, you know, what becomes a, an, a problem, uh, i- i- in a specific society with addiction is not only based on the neurobiological actions, if we're talking still about drugs or substances, of that substance. It's heavily influenced by the availability of the substance too. But my, my little story is I smoked some cigarettes in Paris. I, I, I end, I, I learned why people like to smoke. It was very satisfying to have a cigarette in a Parisian café just, you know, and it's very interesting because the first few times you inhale tobacco, you get dizzy, it's kind of aversive, and it's exactly what you articulated. Despite that, you want to do it again. So I, I, it was just a lot of fun for me, I enjoyed it, and I was disciplined, you know, at some point whenever this was, I came back to the United States, I didn't smoke, um, because I knew it was bad for you. But to this day, 40 years later, every time I go back to Paris, I get cravings. I actually just want to get a pack of cigarettes. I want to, um, f- have that feeling again of inhaling the smoke. But th- the point is of how, you know, powerful these rewarding experiences can be, or reinforcing experiences, and for your audience, it, technically, uh, you know, what I have been taught by some of my psychology colleagues is we use the term reinforcing in a very behaviorally defined way. Something is reinforcing is if it m- the behavior that led to that stimuli, y- it makes you want to do that behavior again. Rewarding means it actually felt, in quotes, good. Um-

Andrew Huberman 54:30 (laughs) Hmm. That's an important distinction.

Robert Malenka 54:31 ... no, they, they actually can be different. Again, as you defined by your friend who his, I forget, it w- I think it was cocaine. Cocaine was highly reinforcing, but it was not necessarily enjoyable or rewarding.

Andrew Huberman 54:44 Mm-hmm.

Robert Malenka 54:45 And isn't that fascinating? I have a, some colleagues in the addiction field, um, I, one of them is retired now, Kent Berridge and Terry Robinson, they, they coin, they distinguish between the terms, uh, wanting and liking. And think about that.

Andrew Huberman 55:04 Mm-hmm.

Robert Malenka 55:05 Liking something means it's something you like, you enjoy.Um, wanting means you want it, but you don't necessarily like it or enjoy it, and that's a description of your friend's experience with cocaine. Some of us have been in destructive relationships where you want that individual, but you're not sure you necessarily like that individual.

Andrew Huberman 55:32 And sometimes people will be in relationships where they actively dislike the other person-

Robert Malenka 55:36 Yeah, isn't that-

Andrew Huberman 55:37 ... which is, which is a bit foreign of a concept to me, but well, it's interesting this, this separation of reinforcing and rewarding, wanting and liking-

Robert Malenka 55:44 Mm-hmm. Yes.

Andrew Huberman 55:44 ... because, um, one of the things that's very prominent in 12-step programs-

Robert Malenka 55:48 Mm-hmm.

Andrew Huberman 55:49 ... is to create rewards around abstaining from the drug or behavior.

Robert Malenka 55:53 Yes. Yep.

Andrew Huberman 55:54 And I should mention that programs like 12-step, when followed, seem to have very high success rates.

Robert Malenka 55:58 Mm-hmm.

Andrew Huberman 55:58 At least that's what Anna Lembke tells me.

Robert Malenka 56:00 Mm-hmm.

Andrew Huberman 56:00 Um, that in some ways they are modifying the wanting and liking. They're splitting the wanting and liking of, you know, alcohol, for instance. Creating a, a liking of sobriety more than the wanting of alcohol, for instance.

Robert Malenka 56:17 That's beautifully put, um, and I think that's right. Um, how that plays out in the neural mechanisms, that as a neuroscientist I'm interested in, man, that's a tough one. Um, but I think that's why th- those programs are pretty successful. It's helping the person make those dissociations. Um, and I, I don't know that much about those programs because I have not seen patients myself for whatever it's been, 27, 28 years, but I think part of them are to help that individual find, as you said, both other sources of liking and reward, um, getting some satisfat- satisfaction and reward from the actual abstinence, being able to cognitively teach themselves that I deserve a pat on the back, I deserve credit, I feel good that I did not take a drink at that party, that I did not use that substance again. And how that plays out in our brains is a really tough one.

Andrew Huberman 57:30 Yeah, those are... Um, the way you described it is exactly right. Those, those programs are highly reinforcing for abstinence behaviors.

Robert Malenka 57:36 Mm-hmm. Yeah.

Andrew Huberman 57:37 Everything from the social connection, which we, we're going to get to social connection as you know-

Robert Malenka 57:40 Mm-hmm.

Andrew Huberman 57:40 ... um, to the way that people start to conceptualize their addict self versus other self.

Robert Malenka 57:46 Mm-hmm.

Andrew Huberman 57:46 It actually involves a splitting of the self in, in interesting ways.

Andrew Huberman 57:50 Um, as long as we're talking about donuts, cigarettes, alcohol-

Robert Malenka 57:55 (laughs)

Andrew Huberman 57:55 ... cocaine, um, I'm curious, uh, before we move to, um, a bit more on neuroplasticity, is there anything that people ought to know about how different substances and behaviors that are addicting might impact the dopamine reward circuitry differently? So for instance, um, we talked about cocaine as having this very rapid onset, big increase in dopamine, then a crash as we know. Um, a certain pattern of kinetics as you describe it. Um, the opioid crisis is, is, you know, an incredibly serious problem right now, uh, as is methamphetamine. Uh, but it sounds like methamphetamine functions a bit like cocaine in terms of its kinetics.

Robert Malenka 58:35 Yes.

Andrew Huberman 58:35 So, an opioid is a very different chemical than cope- cocaine.

Robert Malenka 58:41 Mm-hmm.

Andrew Huberman 58:41 Um, but it sounds like it impacts the dopamine system. Um, is the dopaminergic activity caused by opioids responsible for the addictive properties of opioids, or do people also like the feeling of being under opioids? I personally hate it coming out of surgery. Like, they gave me, they gave me Vicodin once-

Robert Malenka 59:01 Yeah.

Andrew Huberman 59:01 ... um, and I, I hated it.

Robert Malenka 59:03 Mm-hmm.

Andrew Huberman 59:03 I'd rather have the pain-

Robert Malenka 59:04 (laughs)

Andrew Huberman 59:04 ... post-operative pain than take something like, um, you know, Vicodin or, or a Valium or fentanyl or anything like that. To me it's just completely aversive.

Robert Malenka 59:14 Mm-hmm.

Andrew Huberman 59:14 Um, but I realize that there are many millions of people that feel quite differently.

Robert Malenka 59:18 Um, it's a great question. So, I think all the studies both in human beings and pre-clinical animal models, yes, would suggest that the ki- the addictive liability of opioids and psychostimulants, which are cocaine and methamphetamine, have the common final action of causing massive release of dopamine in this target of the dopamine neurons in nucleus accumbens. They do it, if we want to get a little scientifically technical here, via very different mechanisms.

Andrew Huberman 59:59 Mm-hmm.

Robert Malenka 59:59 So, cocaine and methamphetamine, what the drugs known as psychostimulants, um, actually bind to a protein in the brain or a molecule in the brain that is responsible for sucking up. It's a vacuum cleaner, br- su- sucking up the dopamine after it's been released. And cocaine prevents that dopamine from being vacuumed up so the cocaine hangs around longer. Meth not only prevents the dopamine from being vacuumed up, it actually causes the reverse. It actually causes the direct release of dopamine from what we call nerve terminals, from the site where dopamine is released. Opioids work very differently. They actually primarily, not solely, work where the dopamine neurons live. And it's a little complicated and it's not that critical, but they indirectly in- increase the activity within the dopamine neurons themselves, causing a big massive, bigger than normal release of dopamine. So that's one commonality.... but anybody who has used these drugs or read about these drugs, the subjective experience of the drugs are dramatically different, and that's because of the actions they're having, not only in the reward circuitry but throughout the brain. So, and it- it's interesting you talked about Vicodin. I've taken Vicodin because I've had several knee surgeries and things. Like you, I didn't like it. I've te- I've gotten other opioids for pain relief that were great. (laughs) I mean, they took, they took away a lot of pain after my ligament repair, um, and that's a different question that even when you're talking about opioids, all drugs are not cre- or they're not identical. Fentanyl has a much big- larger, um, addictive liability because of its molecular properties and how it's interacting with the opioid system in our brains and the receptors, the actual proteins in the brain that it interacts with. But the subjective experience of opioids, I mean, it's interesting. Uh, some people love it. That's, you know, if we go back in history, as you know, there were the, um, opium dens throughout, um, Asia. Um, there were wars about opioids, the- the- the famous opioid wars between China and the United Kingdom, I mean, showing you how powerful, um, the availability of a substance like an opioid can be. So I'm- I'm going off on a tangent here-

Andrew Huberman 1:02:49 No, I think these are important.

Robert Malenka 1:02:51 ... I apologize, but commonality is dopamine release in the accumbens, but it's a... If you remember what a Venn diagram is, all these drugs have some common actions usually on directly or indirectly causing the massive release of dopamine in the accumbens, but then they have their own individual actions because obviously when you take cocaine or methamphetamine, it's a stimulator. You're- You know, people are grinding their teeth, they're hyped up. For most people, opioids are the exact opposite. You're- I- I mean, in opium dens from the movies I watched (laughs) and watching Narcos and all those TV shows, you're often, you're lying down, you're- you're kind of in a almost a dreamlike state, so very different subjective experiences.

Andrew Huberman 1:03:38 I'd like to just take a brief break and thank one of our sponsors, which is LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means plenty of salt, sodium, magnesium, and potassium, the so-called electrolytes, and no sugar. Now, salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. LMNT contains a science-backed electrolyte ratio of 1,000 milligrams, that's one gram, of sodium, 200 milligrams of potassium and 60 milligrams of magnesium. I typically drink LMNT first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes and while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, and certainly I drink LMNT in my water when I'm in the sauna and after going in the sauna because that causes quite a lot of sweating. If you'd like to try LMNT, you can go to Drink LMNT, that's lmnt.com/huberman, to claim a free LMNT sample pack with your purchase. Again, that's Drink LMNT, lmnt.com/huberman. Yeah,

Andrew Huberman 1:04:51 I had an experience with, uh, opioid recently. Uh, not voluntarily over the Christmas holiday, we went to visit friends and before, um, going to sleep, I wanted some tea and I asked if they had any non-caffeinated tea. So they gave me this tea and, um, and that night I had the most bizarre dreams I've ever had and I slept for 14 hours.

Robert Malenka 1:05:12 (laughs)

Andrew Huberman 1:05:13 The next morning I was like, "What was that tea?" Uh, and I felt off in the morning and I went... It was actually a blue lotus flower tea that is actually illegal in the United States-

Robert Malenka 1:05:23 (laughs)

Andrew Huberman 1:05:23 ... but it is sold and it has morphine-like, um, compounds in it. Um, and I am one of those people that's very susceptible, uh, to even low doses of any kind of novel drug, you know.

Robert Malenka 1:05:34 So- So interesting. Have you ever taken cough syrup with dextromethorphan?

Andrew Huberman 1:05:38 No. See, I avoid that stuff-

Robert Malenka 1:05:40 Well, I, you know, I have-

Andrew Huberman 1:05:41 ... if I can. If I can.

Robert Malenka 1:05:42 I have a tendency when I get a cold, like, it gets into my lungs, I cough a lot. And I think this has been reported. This is my anecdotal experience. It... I'm- I'm confirming what you said. Dextromethorphan is a different sort of opioid and actually some people develop a problem with it. For me, it gives me really bizarre dreams. (laughs) Really bizar- similar to what you were describing.

Andrew Huberman 1:06:05 Yeah. It was a very unusual experience.

Robert Malenka 1:06:06 And that's a whole different conversation about what makes us dream and what the- what are the meaning of dreams. Fascinating. And I hope you covered- Maybe you've covered that in previous-

Andrew Huberman 1:06:14 We have not yet, but we are intending to do a whole series on sleep and dreaming anyway.

Robert Malenka 1:06:18 Yeah, I think that would be a wonderful-

Andrew Huberman 1:06:19 We will definitely get into it.

Robert Malenka 1:06:20 I started out in sleep research, so I have a fondness for it.

Andrew Huberman 1:06:23 Well, drug research and sleep research have a long history-

Robert Malenka 1:06:25 Yeah.

Andrew Huberman 1:06:25 ... of overlap with Allan Hobson's work on LSD and-

Robert Malenka 1:06:28 I worked with Allan Hobson.

Andrew Huberman 1:06:29 Okay. By the way, folks, if you're interested in the-

Robert Malenka 1:06:31 (laughs)

Andrew Huberman 1:06:31 ... relationship between hallucinations and dreaming, Allan Hobson is a good name to start your, uh, your rabbit-

Robert Malenka 1:06:37 In 19-

Andrew Huberman 1:06:38 ... your rabbit hole.

Robert Malenka 1:06:39 I, 19... Oh my God, I'm dating myself. 1970... I can't remember if it was '76 or '77 I worked with Allan Hobson as an undergraduate.

Andrew Huberman 1:06:50 At Harvard Medical School.

Robert Malenka 1:06:51 Yeah. No, I, as an undergraduate at Harvard. He was at Harvard Medical School.

Andrew Huberman 1:06:54 Right, right. Amazing. I love his writing and I learned a lot from it.

Robert Malenka 1:06:57 Yeah, yeah. Yeah. Very-

Andrew Huberman 1:06:57 He was really ahead of his time.

Robert Malenka 1:06:59 Yes, he was.

Andrew Huberman 1:06:59 'Cause, uh, we'll get to such-

Robert Malenka 1:07:01 I was a sh- Nobody would... Anybody who knows me won't believe this, but I, back then, I was a very shy, insecure, you know, 20-year-old kid who-

Andrew Huberman 1:07:08 I would not have guessed.

Robert Malenka 1:07:09 Oh. I, and even in medical school, I a- I literally was not confident of my opinions at all. I was very shy, was n-... thought all of the ideas I had must be obvious and I should never say them out loud.

Andrew Huberman 1:07:23 Well, do you mind if I ask-

Robert Malenka 1:07:24 (laughs)

Andrew Huberman 1:07:24 ... um, since, since you raised this.

Robert Malenka 1:07:25 (laughs)

Andrew Huberman 1:07:26 I think it's really important. I mean, you, you have this incredible, uh, career track record. Um, I, you know, you're adored by your colleagues.

Robert Malenka 1:07:34 (laughs)

Andrew Huberman 1:07:34 You're highly respected. You've won just about every reward, award there is to win in neuroscience.

Robert Malenka 1:07:38 Very nice of you.

Andrew Huberman 1:07:38 So was there something in particular that, um, like, was it an overnight thing where one day you woke up and thought, "You know, I actually believe in myself."

Robert Malenka 1:07:46 (laughs)

Andrew Huberman 1:07:46 But if you wouldn't mind sharing that-

Robert Malenka 1:07:48 Sure.

Andrew Huberman 1:07:48 ... 'cause I think before we t- get back into some of the, the science, I, you know, this i- science is a human endeavor and, and most people listening are-

Robert Malenka 1:07:54 Yeah.

Andrew Huberman 1:07:54 ... probably not scientists, but I think everybody deals with these issues of-

Robert Malenka 1:07:58 Yeah.

Andrew Huberman 1:07:58 ... of, of self-doubt and s- people appear to have varying levels of confidence, but, uh, what, what happened?

Robert Malenka 1:08:05 Uh, it's a, it's a thank you for asking. Um, it wa- and though for me, it was a very gradual process, and I'm, I'm not... As a, as an undergraduate, as a medical student, even as a post-doc, yeah, I was very unsure of my ideas, of my intellectual abilities, of whether what I was thinking was really, you know, worthwhile. So it was a very gradual process. I think it, m- the increase in my confidence I think began when I was a post-doc, which is a training period after you've received a PHD or an MD where you get additional research training, and I worked with a guy named Roger Nicol at UCSF, and Roger was a very for- intellectually intense, very forceful individual, and I got involved in a field where, I mean, people... A little bit of a tangent. Your, your, your listeners may think that scientists are these geeky individuals wearing white coats with no passion or emotion, and nothing could be further from the truth. The most successful scientists I know are pretty passionate and pretty intense about what they're working on, and driven, um, I mean, and this is a gross generalization. So anyhow, during my post-doc, I started getting involved in a topic where there were vigorous arguments about phenomenology we were studying, so I had to develop a tougher and thicker skin. I had to be able to argue my side of, of the hypotheses we were generating. So I, it started developing as a post-doc, and then it slowly evolved as an assistant professor, um, and for your listeners who don't know, I don't like to admit this, but I'm in my late 60s.

Andrew Huberman 1:10:08 (laughs)

Robert Malenka 1:10:08 I've been running my own lab for almost 40 years, um, so I have been... Um, so gradually as an assistant professor, I realized, hey, I can do this. I can do science. I can write papers that my colleagues seem to be interested in, and then gradually, you know, over then the next 10, 20, 30 years, I g- I gained more and more confidence. I, so for me, i- it was this very gradual, um, buildup of many different experiences where I developed some confidence that, you know, not all of my ideas are great. Of course they're not, but i- it's okay to voice my opinion, it's okay to state my ideas and why I believe this and why I don't believe that, so that was my experience.

Andrew Huberman 1:11:03 Thank you for sharing that-

Robert Malenka 1:11:04 Sure.

Andrew Huberman 1:11:04 ... because I think, uh, you know, people struggle with the, that very issue, and, um, clearly showing up again and again over a long period of time is helpful, but as you said, you know, tr- learning to trust one's ideas, just a brief anecdote, uh, when I was, um, coming up in neuroscience a few years behind you, um-

Robert Malenka 1:11:23 20 years behind me. (laughs)

Andrew Huberman 1:11:24 Not too ma- not too many, I mean-

Robert Malenka 1:11:26 Two decades behind me. (laughs)

Andrew Huberman 1:11:26 ... but, um, but I re- recall the incredible number of high profile papers on neuroplasticity and long-term potentiation-

Robert Malenka 1:11:35 Mm-hmm.

Andrew Huberman 1:11:35 ... long-term depression. These are terms, uh, related to the modification of synapses, um, that Rob Malenka and Roger Nicol pioneered a big segment of that work-

Robert Malenka 1:11:45 Yes.

Andrew Huberman 1:11:45 ... and I remember seeing your names on papers and I thought Roger worked for you.

Robert Malenka 1:11:49 (laughs)

Andrew Huberman 1:11:49 (laughs) Sorry Roger.

Robert Malenka 1:11:50 I'd love, I'd love to hear that. I love to hear that. (laughs)

Andrew Huberman 1:11:53 I was under the impression he worked for you-

Robert Malenka 1:11:55 (laughs)

Andrew Huberman 1:11:55 ... and only later did I learn that you were, uh, his post-doc, so-

Robert Malenka 1:11:58 And then, and then we collaborated as equals.

Andrew Huberman 1:12:01 Right. You became peers very quickly.

Robert Malenka 1:12:02 Very quickly.

Andrew Huberman 1:12:03 Yeah, so you've had a-

Robert Malenka 1:12:04 And Roger, you know, I-

Andrew Huberman 1:12:05 Roger is wonderful.

Robert Malenka 1:12:06 I did have the confidence even as a post-doc, any- actually even as a grad student, even though I was a little insecure about my ideas, I wanted to be treated as an equal. That's the one thing I did have. I never felt that I was working for somebody else. I always felt that I was working for myself and that we were colleagues, um, even though my mentors are m- who had more experience and I could learn from them, but-

Andrew Huberman 1:12:31 I like that, that you're working-

Robert Malenka 1:12:32 ... and that's all.

Andrew Huberman 1:12:32 ... for yourself even though you have mentors.

Robert Malenka 1:12:34 Yeah.

Andrew Huberman 1:12:34 I, I think there's some, there's some real gems in what you just described-

Robert Malenka 1:12:38 Yeah.

Andrew Huberman 1:12:38 ... so thank you for-

Robert Malenka 1:12:39 Sure.

Andrew Huberman 1:12:39 ... taking the time to do

Andrew Huberman 1:12:40 that.

Robert Malenka 1:12:40 Sure.

Andrew Huberman 1:12:41 I'd like to discuss one aspect of reward circuitry that I don't think most people think about, right?

Robert Malenka 1:12:48 Mm-hmm.

Andrew Huberman 1:12:48 It's fairly straightforward, I know nowadays I, I like to think more people know what dopamine is and understand it-

Robert Malenka 1:12:53 Yeah.

Andrew Huberman 1:12:53 ... thanks to your work and Anna's work and some discussions that have taken place on our podcast and other podcasts-

Robert Malenka 1:12:58 Mm-hmm.

Andrew Huberman 1:13:00 ... but, you know, it's all too often we think dopamine, reward, wanting, liking drugs, okay all of that is great-

Robert Malenka 1:13:06 Mm-hmm.

Andrew Huberman 1:13:07 ... but what about the truly adaptive stuff, right? Because it's, it's, um, easy to fall into a discussion around dopamine of, you know, the things that are bad for us-

Robert Malenka 1:13:16 Mm-hmm.

Andrew Huberman 1:13:16 ... but what I'm thinking about here is social interaction.

Robert Malenka 1:13:19 Yeah.

Andrew Huberman 1:13:20 Um, clearly we are a social species, and a lot of your work in the last, um-... decade and a half or so-

Robert Malenka 1:13:27 Yeah, yeah.

Andrew Huberman 1:13:28 ... has focused on the relationship between the reward circuitry, which you beautifully described for us, and social interaction and connection.

Robert Malenka 1:13:37 Mm-hmm.

Andrew Huberman 1:13:37 And where I'm going with this is ultimately, this has huge implications for autism and autism spectrum disorders. I don't know if nowadays, is it okay?

Robert Malenka 1:13:47 I, I-

Andrew Huberman 1:13:47 You're not supposed to call autism a disease, is that right? You hear about neurotypical and neuro-atypical.

Robert Malenka 1:13:52 (laughs)

Andrew Huberman 1:13:52 But is, but I have friends who have children who are severely autistic.

Robert Malenka 1:13:57 Yeah.

Andrew Huberman 1:13:57 And, um, I don't know many parents who would elect to have a severely autistic kid.

Robert Malenka 1:14:02 Mm-hmm.

Andrew Huberman 1:14:03 And so those people often will talk about it as autism or a child having autism. So first of all, before we get into -

Robert Malenka 1:14:10 Mm-hmm.

Andrew Huberman 1:14:10 ... the social piece, maybe because I just tabled it, w- what is, how are, are we supposed to talk about autism nowadays?

Robert Malenka 1:14:17 I, I, I am very interested in the pathophysiology of what the medical profession terms autism spectrum disorder. As you pointed out, the individuals living with an autism spectrum disorder are quite heterogeneous. And it, it, it can range from individuals with severe intellectual impairments and quite severe impairments in social interactions, impairments in sensory processing, impairments in, in lots of different aspects of our behaviors that are important. And I think nobody would say, would argue those individuals on the severe spectrum do not have some sort of, in quotes, disorder. The issue we have to be sensitive to is it's, it's a heterogeneous disorder like many brain issues that psychiatrists deal with, like depression. We all, um, like obsessive compulsive disorder, like various anxiety disorders. It's always on a continuum and a spectrum. So for autism spectrum disorder, there are individuals who are high functioning, who one could argue have a different style of interacting socially, may have a different way of processing sensory information, but who have, who would prefer not to be viewed as having an illness, but rather would be viewed as having a different style of living and interaction. And I think we need to respect that. So the challenge is, again, not oversimplifying a complex heterogeneous disorder, um, and both being respectful of the people who don't want to be defined as having a neuropsychiatric or brain disorder while equally being respectful of people like your friends with severely impaired children who deserve help, who deserve research. And it's a tough one because my understanding from, to be honest, just reading articles in the lay press and going to websites from organizations that philanthropically support research related to autism, within that community of individuals who are not researchers but who are, have family members or are themselves dealing with some degree of autism spectrum disorder, there's disagreements about how to, what terminology to use, how to deal with them. Mm-hmm. And it's complicated. I think we just have to respect everybody. And if you're interacting with individuals, you, you know, I think it's appropriate. What do you prefer?

Andrew Huberman 1:17:17 Mm-hmm.

Robert Malenka 1:17:17 Um, I do know as a medical professional, there, and especially when you're dealing with children, there are children who need help. And I, I, I, we're not doing them a service by saying they don't have an issue that we should be helping them with and working on. So I hope that answers your question.

Andrew Huberman 1:17:38 Yeah, beautifully.

Robert Malenka 1:17:39 Um-

Andrew Huberman 1:17:39 I think it beautifully answers it and encompasses all sides, um, so that we can move forward. And I think we'll, so as we use the term autism or children or people with autism, um, that's what we're referring to.

Robert Malenka 1:17:51 I, I think people are very sensitive, especially those individuals who are neuro-atypical, who m- and previously might be diagnosed as autism spectrum disorder, but would prefer to not be labeled as having a brain illness. That, that's fine. Um, it's kind of once you are an adult, you can make that decision for yourself. Uh-

Andrew Huberman 1:18:14 We certainly have colleagues at Stanford and elsewhere who-

Robert Malenka 1:18:16 Of course. (laughs)

Andrew Huberman 1:18:17 ... at least by my non-clinical assessment, seem to fall-

Robert Malenka 1:18:19 Of course.

Andrew Huberman 1:18:20 ... somewhere on that spectrum.

Robert Malenka 1:18:21 And again, it's a continuum-

Andrew Huberman 1:18:22 Yeah.

Robert Malenka 1:18:22 ... just like, you know, the experience of depression is in a, a continuum.

Andrew Huberman 1:18:26 Mm-hmm.

Robert Malenka 1:18:26 But, all right, but then-

Andrew Huberman 1:18:27 Right, and as with depression, you wouldn't love a child or an adult any less because they have depression.

Robert Malenka 1:18:31 Yeah, yeah, yeah.

Andrew Huberman 1:18:31 Nor would you love a child or adult any less, uh, because of, uh, expression of some autism symptoms.

Robert Malenka 1:18:36 So I, I know the point. I, people don't, you know... And so we, we have been, we are being trained in the medical profession to be very fir- you know, and our society is going this way too, very careful with the terms we use and the labeling of individuals. Um, so you, you know, I've been taught you can say individuals living with an autism spectrum disorder. Um, some people don't like using the term, "Oh, that individual is autistic," because that has some, can have some, I don't want to say derogatory meaning, but some labeling kind of. But you know, sometimes this gets out of control too, as we both know.

Andrew Huberman 1:19:18 Righet. Well, for sake of fluid conversation-

Robert Malenka 1:19:20 Yeah.

Andrew Huberman 1:19:20 ... we will do our best.

Robert Malenka 1:19:21 (laughs)

Andrew Huberman 1:19:21 But, um, we will acknowledge from the outset that we are well-meaning but far from perfect-

Robert Malenka 1:19:26 Yeah.

Andrew Huberman 1:19:26 ... in, in how we'll handle this.

Robert Malenka 1:19:27 Well put. Well put.

Andrew Huberman 1:19:29 So in thinking about social interactions and leaving aside anything related to autism for the moment-It appears that the circuits in the brain that mediate the desire to spend time with others of the same species, maybe even with other species like a dog-

Robert Malenka 1:19:43 (laughs)

Andrew Huberman 1:19:43 ... um, are fairly hardwired but modifiable. They, we were born with the capacity to build them up.

Robert Malenka 1:19:51 Mm-hmm.

Andrew Huberman 1:19:52 Um, and that social behavior is highly rewarded. Is it rewarded through the dopamine system? And what, if any, involvement is there of the serotonergic system? And we haven't talked about serotonin yet, but I'd love to bring up serotonin at this point. Maybe you could educate us a little bit about serotonin because, um, gosh, if dopamine is fascinating, serotonin is at least as incredible.

Robert Malenka 1:20:18 (laughs) Um, yeah, great question. So I, I think for me, the easiest way for me to answer it is actually just tell you my research history and how a lab like mine at Stanford that at one point was studying what I, what you and I would call fairly hardcore molecular mechanisms of neuroplasticity. How do connections between nerve cells change and what molecules are changing and r- pretty hardcore molecular stuff. How did I end up studying social behaviors in mice and what I hope we'll end up talking about even developing behavioral models of what I will define as empathy in mice. The answer is very simple. My lab was working on roles of classic dopamine reward circuitry and how it changes in models of addiction. We haven't talked about depression, models of depression, because just intuitively, hopefully your listeners can understand if one component of depression is what we call anhedonia, the inability to experience reward. You know, eating a donut is no longer satisfying, having sex is no longer that much fun, which is a component of depression. If there's a mechanism in the brain that tells you something is rewarding, by definition, that's not functioning normally in severe depression. So we were doing models of depression to figure out how the dopamine reward circuitry was changing, as were many other labs. We were studying addiction. Those were the obvious ones. And I mean, it might be entertaining to, to your audience to thi- learn how academic scientists think. I was thinking those are fascinating topics. They're pretty competitive. Um, lots of other labs were working on it. And I started thinking what other experiences might be modifying the reward circuitry. I actually made some attempts to look at feeding behavior, but I don't want to, I mean, we actually never pursued that for a variety of reasons. And that's obviously important because of there is an obesity epidemic in this country. Uh, and we can talk about how the reward circuitry and some of the things we've learned from our studies of addiction may be helpful to understanding obesity. But back to social interaction. I started thinking, well, for most of us, uh, what I call a prosocial, nonsexual experience is highly reinforcing. Um, Andrew, you're a pretty social guy. I'm a pretty social guy. Most of the time I'd rather go to a movie, a sporting event, a dinner with friends. Um, it's, you know, actually for me, the most meaningful component of my life other than spending time with my children is spending time with my close friends. Um, and I started thinking, well, why is that? Why do I have such a good time going to a ball game with my best friend or going out to dinner with another couple, um, and interacting? It's because, well, it's highly reinforcing and if it's highly reinforcing, it must involve the reward circuitry. And then I started thinking evolutionarily it makes a lot of sense because if you are part of a social species, there's a lot of evolutionarily, uh, uh, a lot of advantages for your survival to be hanging out with other members of your species in a non-aggressive way. It can increase your likelihood to find a mate and reproduce. It can protect you from predators. I mean, that's why any of your listeners who ever watch, um, you know, wildlife shows or National Geographic shows, there's a reason all these animals hang out together. (laughs) It's for protection from predators. So there are all these reasons. So about whenever it was, 13 or 14 years ago, my lab decided to start looking at how the reward circuitry may play a role in what I am going to call positive prosocial nonaggressive interactions. Um, another word we use is just sociability. Um, and for a variety of reasons back then, this is go- this is at least 13 years ago, maybe 15 years ago, a postdoc joined my lab named Gul Dolen. She's now a professor at Johns Hopkins. Um, and she had an interest in oxytocin. Um, and as your listeners know, um, oxytocin is this evolutionarily conserved neuropeptide that's very important for parturition, the having a baby born, for milk being produced. And it's gotten a lot of attention as a potential love neuropeptide. It's something that is released in our brains during a positive social interaction. There's a, a well-known researcher in social behavior and bonding research called Larry Young, and he did some very important, now somewhat classic work studying a species called the vole, in particular the prairie vole, and prairie voles-...are a species where they mate for life. It's called pair bonding, so one vole will find another vole, they basically get married, they have kids, and they're, they hang out together for the rest of their life.

Andrew Huberman 1:26:01 No divorce, no 50% divorce rate. (laughs)

Robert Malenka 1:26:03 No, no 50 di- 50% divorce rate. And what Larry elegantly showed, um, in part, in early days in collaboration with a guy named Tom Insel, who is a famous academic psychiatrist, um, they showed that oxytocin action within the nucleus accumbens, within this reward circuitry, was r- required and really important for this monogamous pair bonding. Having said that, there was just a paper that called into question that, but th- that's they're talking-

Andrew Huberman 1:26:36 But there's 30 years of research prior to that.

Robert Malenka 1:26:38 Yeah, yeah. And, and-

Andrew Huberman 1:26:39 I'm glad you brought that up because, uh, we'll keep this contemporary and the, th- the reality is that that recent paper got a lot of attention.

Robert Malenka 1:26:45 You know the paper I'm talking about.

Andrew Huberman 1:26:46 Yeah, that maybe oxytocin isn't playing as prominent a role in pair bonding-

Robert Malenka 1:26:49 Yeah, exactly.

Andrew Huberman 1:26:49 ...as people had thought, and yet, folks, uh, th- that could be true. We have to be scientific about this and be open-minded, but there's, you know, three decades of work-

Robert Malenka 1:26:59 Yeah, and-

Andrew Huberman 1:26:59 ...uh, that, that speaks to the contrary, so I think we wanna be a li- we wanna weigh the evidence.

Robert Malenka 1:27:04 We w- yeah, exactly. And again, the, the investigators who presented the work saying oxytocin may not be as important, there are limitations to the manipulations they did, which they would agree with. So I'm just telling you, so Gul Dolen was a postdoc in my lab, and we decided, we formulated a project to look at the actions of oxytocin in the nucleus accumbens in mice. And the reason we study mice is you... They're what are known as a genet- genetically tractable organism. We have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry, the actions of neuromodulators like dopamine and serotonin and oxytocin in ways that we can't do in other species, um, and I'm gonna get back to dopamine in a second. And what we found was that oxytocin action in the nucleus accumbens was indeed important for promoting sociability, probably for promoting the reinforcing component of a social interaction, and that surprised us. You know, it was like, wow. It's, it's, oxytocin seems to be causing, enhancing the release of serotonin in the nucleus accumbens, and that wil- will, I'm... Perhaps we'll get to this. That led me off on a whole series of experiments trying to figure out how serotonin works, studying this drug we may talk about called MDMA, which is ecstasy or Molly, which actually causes release of serotonin. So we did that work and that got us working in serotonin. Simultaneously, there were some other papers reporting that dopamine release in the accumbens, that dopamine is released in the accumbens during a social interaction, a positive, non-aggressive social interaction. Truth be told, it may also be released during an aggressive interaction.

Andrew Huberman 1:29:08 Some people like to fight.

Robert Malenka 1:29:10 Some people like to fight, and the difference here is the dopamine release and its role in social interactions, it's not specific only for social interaction, as we have talked about. But nevertheless, that led my lab and other labs to do a series of papers. W- I'm talking about the field now showing that, and I'm giving you a lot of information here, so how might dopamine release happen during a non-aggressive social interaction? It turns out that oxytocin is not only released in the nucleus accumbens, it's released in the d- home of the dopamine neurons, in the VTA. So my lab and another lab from Northwestern showed that oxytocin can actually modulate dopamine neuron activity in the ventral tegmental area. So I hope I'm making sense here. I don't wanna get too technical.

Andrew Huberman 1:30:06 Well, no, I think it's-

Robert Malenka 1:30:06 But it just shows how the, you know, we discuss these neuromodulators like dopamine. I just brought in oxytocin. We're gonna talk about serotonin in a second. Unfortunately for your listeners, they don't work in isolation. They commun- they influence each other in ways that I think it's important for us to understand and elucidate. Um...

Andrew Huberman 1:30:30 That is not too much technical detail-

Robert Malenka 1:30:32 Okay.

Andrew Huberman 1:30:32 ...um, and I think it's wonderfully rich with areas for us to discuss. And I'm so very glad that you brought up that neither dopamine nor serotonin nor oxytocin work in isolation.

Robert Malenka 1:30:43 Mm-hmm.

Andrew Huberman 1:30:43 Because all too often, and admittedly sometimes even on my podcast-

Robert Malenka 1:30:47 (laughs)

Andrew Huberman 1:30:47 ...I'll talk about these things in isolation as a way to try and simplify them a bit, but there's just no way that the brain works that way, you know, for instance, turning on dopamine and turning off serotonin. It's a weighting of, of inputs. And I think that serotonin-

Robert Malenka 1:31:01 Exactly.

Andrew Huberman 1:31:02 ...uh, perhaps I should frame it this way. Just as often as dopamine is framed as this reward molecule and pleasure and dopamine hits, all too often, I think, in the popular press, serotonin is discussed, and oxytocin too for that matter, as this kind of warm, feel-good-

Robert Malenka 1:31:18 Mm-hmm.

Andrew Huberman 1:31:18 ...everything's mellow, um, you know, not really associated with r- reward and reinforcement.

Robert Malenka 1:31:23 Mm-hmm.

Andrew Huberman 1:31:24 And, uh, of course, it's not that simple. So when it comes to social interactions, it sounds like oxytocin and serotonin are playing a prominent role-

Robert Malenka 1:31:32 Mm-hmm.

Andrew Huberman 1:31:33 ...also in the accumbens.

Robert Malenka 1:31:34 Mm-hmm.

Andrew Huberman 1:31:35 Um, and that dopamine is, is activated too.

Robert Malenka 1:31:38 Yes.

Andrew Huberman 1:31:38 Do I have that right? Okay. So, um, I don't wanna take us too far down the rabbit hole of neural circuit function, but that, to me, um, makes at least a brief discussion about the nucleus accumbens itself interesting. Like, okay, so I'm thinking nucleus, I know that means a pile of neurons.

Robert Malenka 1:31:55 (laughs)

Andrew Huberman 1:31:55 An aggregation of neurons that's talking to this ventral s- striatum. So we got a bunch of neurons-

Robert Malenka 1:31:59 It's, it's part of the ventral striatum.

Andrew Huberman 1:32:00 Part of the vent-

Robert Malenka 1:32:00 It's like, it's a subdivision of it.

Andrew Huberman 1:32:02 Excuse me.

Robert Malenka 1:32:02 Yeah.

Andrew Huberman 1:32:02 I misspoke.

Robert Malenka 1:32:03 Yep.

Andrew Huberman 1:32:03 Um, yeah. It's part of the ventral striatum and it's, um...... and, and the neurons there can be active and communicate with other brain areas. But we're talking about a lot of nuance of function.

Robert Malenka 1:32:13 Oh, man.

Andrew Huberman 1:32:14 So, so I'm not-

Robert Malenka 1:32:15 I'm smiling. I don't know if your audience is-

Andrew Huberman 1:32:16 Yeah.

Robert Malenka 1:32:17 ... going to see me smile because it's so... Uh, I sometimes go to bed feeling it's so complicated.

Andrew Huberman 1:32:22 Right.

Robert Malenka 1:32:22 Oh my gosh.

Andrew Huberman 1:32:23 It is.

Robert Malenka 1:32:23 (laughs)

Andrew Huberman 1:32:24 And yet, and yet could we say that within the nucleus accumbens, there are neurons that are acting as, um, accelerators and brakes?

Robert Malenka 1:32:31 Mm-hmm.

Andrew Huberman 1:32:31 Um, I mean, is there a simple analogy that perhaps while not exhaustive can still be true?

Robert Malenka 1:32:37 Sure.

Andrew Huberman 1:32:37 'Cause that's always the goal on this podcast.

Robert Malenka 1:32:38 Sure, sure.

Andrew Huberman 1:32:38 There's no way we can be exhaustive, but we want to be as accurate as possible.

Robert Malenka 1:32:42 So a very influential hypothesis which has guided my thinking, and again, th- the trick, I mean, you know, you have done a wonderful job of communicating complex scientific topics to your podcast audience, and I congratulate you on that.

Andrew Huberman 1:33:00 Thank you.

Robert Malenka 1:33:00 Um, and it's really-

Andrew Huberman 1:33:01 We try.

Robert Malenka 1:33:02 It's