In this episode, my guest is Robert Malenka, MD, PhD, a professor of psychiatry and behavioral sciences at Stanford School of Medicine who has made numerous seminal discoveries of how the brain changes (neuroplasticity) in response to learning and in response to rewarding and reinforcing experiences. We discuss the brain’s several reward systems involving dopamine and serotonin and how these motivate us to seek out specific behaviors and substances. We discuss how these reward systems are modified based on context and our memories, and how they can be hijacked toward maladaptive drug seeking in addiction. We also explore how reward systems influence social connections, oxytocin and empathy and how that applies to our understanding of autism spectrum disorders. This episode should be of interest to those interested in neuroplasticity, social bonding, addiction, autism learning and motivation.
For the full show notes, visit hubermanlab.com.
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Timestamps
(00:00:00) Dr. Robert Malenka
(00:02:37) Sponsors: ROKA & Levels
(00:05:21) Dopamine & Reward Circuitry
(00:11:31) Reward, Arousal, Memory & Dopamine 
(00:17:34) Context, Cues & Dopamine Modification
(00:25:38) Memory & Reward Scaling
(00:30:50) Dopamine, “Addictive Liability” & Route of Administration 
(00:39:07) Sponsor: AG1
(00:40:04) Drugs of Abuse & Brain Changes; Addiction & Individual Variability
(00:50:51) Reinforcement vs. Reward, Wanting vs. Liking
(00:57:500 Opioids, Psychostimulants & Dopamine
(01:03:38) Sponsor: LMNT
(01:04:51) Self-Doubt, Confidence & Career
(01:12:40) Autism Spectrum Disorder
(01:19:29) Pro-Social Interaction & Reward; Oxytocin, Serotonin & Dopamine
(01:30:30) Nucleus Accumbens & Behavior Probability
(01:38:28) Reward for Pro-Social Behavior
(01:43:13) Social Media & “Addictive Liability”; Gambling
(01:52:17) Pain, Social Behavior & Empathy
(02:02:19) Empathy Circuitry, Dopamine & Serotonin 
(02:10:07) Autism Spectrum Disorder & Social Interactions, Empathy
(02:17:23) MDMA, Serotonin & Dopamine; Addiction & Pro-Social Effects
(02:28:13) Autism Spectrum Disorder, Social Behavior, MDMA & Pharmacology
(02:37:18) Serotonin, MDMA & Psychedelics 
(02:40:16) Psychedelics: Research & Therapeutic Potential
(02:47:57) Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Social Media, Neural Network Newsletter
Title Card Photo Credit: Mike Blabac
Disclaimer

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.

Robert Malenka is a professor of psychiatry and behavioral sciences at Stanford University School of Medicine.

He is both a medical doctor and 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.

Malenka's research is considered central to the textbook knowledge about how reward systems in the brain are organized and function.

Malenka's research over the last 10 or 15 years has merged what was once 2 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.

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.

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.

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 0 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.

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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 in psychedelics and what they're doing and potential for mental health.

There are just so many things that 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 learned a tremendous amount from you by observing you and from being your colleague.

You're making me blush and I don't blush easily.

And I will say as well, you've also trained an enormous number of incredible scientists, Karl Deisseroth, the Karl Deisseroth.

Ana Lemke always speaks incredibly highly of you as a mentor and I'm somebody she's learned a tremendous amount from and pretty much anyone that's worked on neuroplasticity, on dopamine and reward systems, addiction, And now in the fields of autism and soon psychedelics as well, references as you often, and you've been mentioned many times before on this podcast, if not by name, by work.

I'd love to kick off the conversation 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.

People think about dopamine as pleasure, dopamine reward.

For the novice, how would you frame the dopamine system?

I mean, it does a bunch of different things in different areas of the brain and body, but to you, 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 more or less put value on our experiences?

As you point out, dopamine is 1 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.

Its best well-known function is in what we call the brain's reward circuitry.

And when we use the term circuit, what we really mean is 1 part of the brain communicating with another part of the brain, because the brain is this very complex, you know, it's 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.

Dopamine was discovered, oh I should know this, many decades ago.

As I said, the major chemical messenger molecule in the so-called 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.

And before getting into the details of dopamine and its function in the reward circuitry, I think it's useful to talk about 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.

And if you think about the evolution of our species, everything is driven by developing mechanisms that increase our survival.

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 sugary, high-fat laden foods are highly reinforcing and rewarding.

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.

What evolved is a mechanism to tell our 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 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 event, this stimulus, it could be an external stimulus, like I said, a Krispy Kreme donut, which I happen to love and I have to be very disciplined so I don't eat too many of them.

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.

So now we need to get into a little bit of detail.

Neuroscientists use these very unfriendly terms to describe different brain regions.

So the home of dopamine cells, or brain cells are called neurons.

So the home of dopamine neurons are in a part of the brain, sort of what we call the lower midbrain.

The dopamine neurons that are part of the reward circuitry are found in this area called the ventral tegmental area, which I'm sorry to have to use such technical jargon.

And we call it the VTA, that's the acronym.

I think the Roof of the midbrain is the tectum, it means roof, and the base of the midbrain, it means floor, which is tegmentum.

think that's the, so there's a rationale, but it doesn't help much at all to know the names.

And in fact, you are absolutely correct, and I always forget that.

And then, which I once did back in the early 80s, but I've forgotten everything I taught.

Anyhow, so these dopamine neurons, and we can talk about other types of dopamine neurons, they send messages, what we call projections, using telegraph wires that we call axons.

They send projections to many different brain regions.

The key 1 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 how that name evolved the nucleus accumbens

sure I should know because I've been studying it for 30 years, but I have never looked up the genesis of that name.

Well, the fortunate thing about this podcast is it's both on audio platforms like Spotify and Apple, but also on YouTube.

And so now we can be absolutely sure that somebody has put it into the YouTube comments underneath this episode and therefore everyone will learn, including us.

So I don't know the origins of the word nucleus accumbens.

And it's a gross oversimplification, but it's the activity of these dopamine neurons in the ventral tegmental area that then cause the release of this powerful neuromodulator dopamine in the nucleus accumbens, which is part of another brain structure with a tough to remember name called the ventral striatum.

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, 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 it tells us is that there's something really important happening in our environment.

So, could we say that it cues the arousal system?

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, 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 wanna remember that.

It could be a highly rewarding experience, like a source of food.

For me, it's a critical, I like all donuts.

any 1 manufacturer of 1 donut versus the other.

That's why I never eat them because I like them so much.

But because that was an important event for my survival, this reward circuitry, yes, it stimulates my arousal system.

It also has very close ties to memory systems.

And to go off on a little bit of a tangent, I think the 1, I don't want to say it's a mistake.

I think 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 the system during painful stimuli and during aversive stimuli, which again are really important for you to be aware of to say, Oh my God, that's really bad for me.

And so the dopamine system, this reward circuitry and its subcomponents that maybe perhaps signal more salience or aversion in the environment are closely tied to arousal systems and memory systems.

Again, hopefully for somewhat obvious reasons, you wanna remember powerfully reinforcing events in your life, as well as powerfully emotionally or physically painful events in your life.

So I hope I answered your question to a modest degree.

Far better than a modest degree, that's an excellent description of the dopamine system from a true expert.

And the question I have is about some of the context and nuance of the system, but in sort of real world terms, how should I think about this?

Even in My training as a neuroscientist, I know neurons can be a little active, a lot active, everything in between.

They can be active over long periods of time or short periods of time.

I actually don't have a craving for sweet things, but Donuts is an exception.

But if I were to see just a little piece of a glazed old-fashioned donut versus a full glazed old-fashioned donut, could I expect that more dopamine is released to the anticipation of the complete donut.

And then the other question is how does context influence the dopamine system?

For instance, if I'm very full, a glazed old-fashioned donut might be aversive to me.

Whereas if I'm just a little bit hungry or if I'm actually more on a schedule of rewarding myself for abstaining from sweet fatty foods, then abstaining from the food might be its own form of reward.

Yeah, I mean- And so to me, the dopamine system seems incredibly simple and yet incredibly prone to immediate context and the kinds of nuance that, 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 have good health metrics and maybe have a certain aesthetic qualities to our body, but we also want the donut.

And so how does a system as simple as a 1 neuromodulator system and the VTA to nucleus accumbens and with some connections to the memory area, how does it balance all of that information in real time?

To me, that's just like staggeringly complex, but also incredibly interesting.

I think you beautifully put, very eloquent description.

You just said it, it's staggeringly simple, simultaneously staggeringly complex.

And you asked several different questions.

And that's 1 of the reasons I became interested in the dopamine reward circuitry is, as you know, as a colleague in the academic neuroscience world, but your listeners probably don't, I started out my career studying very basic mechanisms of plasticity.

And what makes the brain different than the computer hardware is 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.

And so you gave the example of donuts and feeding and I'll answer your question about the cues.

Yes, it's I used to give the example of Thanksgiving.

You know, in the morning of Thanksgiving, all, for most of us in the United States, 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 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 of your memory system sort of talking to, in a simple way, your reward circuitry.

1 could almost say this craving, which maybe we'll talk about in the context of addiction.

And then to 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 repetitive, 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 again, my other favorite example is any of us who have been in an intimate relationship knows that the love of your life can turn to the bane of your existence in 20 seconds.

And again, that doesn't happen magically.

This person who you crave, who you love, does something, and 2 minutes later, your brain is saying, oh my God, I may have to break up with this person, or This is an incredibly painful 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 is everything about how this powerful neuromodular choice system that uses dopamine works.

It's because the inputs onto these dopamine neurons, the other nerve cells that are driving the activity of the dopamine neurons, And I've actually studied this in my lab at Stanford University with a colleague, you know well, Li-Chun Luo, who's a world-class neuroscientist.

We've studied the complexity of the neuroanatomy of the dopamine system.

And these dopamine neurons in the ventral tegmental area, the source of the reward circuitry dopamine, are receiving inputs from all over the brain.

They're receiving indirectly or directly inputs from visual areas, from somatosensory areas, and I'm not giving you a really good answer because that's 1 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 going to get back to, of the donut or of a drug.

How this neuromodulatory system responds?

Similarly, the nucleus accumbens, 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.

It receives inputs from an area called the hippocampus, which you may have covered in previous podcasts, which is very powerful, very important for memories, both establishing new memories.

You want this system, this dopamine reward circuitry to be very connected to memory systems.

So 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 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, is important for decision-making, for planning our activity, and I could go on and on.

Well, can we talk about prefrontal cortex for a moment?

Because 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, it's, as we say, monosynaptically, as you and I know, 1 connection away from structures like the amygdala, 1 connection away from structures like the nucleus accumbens.

In other words, prefrontal cortex to me is every bit as ancient as some of these other structures that we think of as more ancient.

And really the whole ancient evolved thing gets a little bit dicey because certain areas are like the prefrontal cortex are more elaborated in humans.

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 seems to know, okay, we're recording a podcast now and there are certain rules, there are certain things that we're going to do and not do.

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 relationship example is that, yes, at 1 moment we can adore somebody and another moment later, if they do something or don't do something, we can be incredibly frustrated with them.

Hopefully that doesn't happen too frequently.

But I think we've all had the experience of a donut, an event, or a person actually looking different to us from 1 moment to the next, hopefully not at random, right?

And so to me, it seems like 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 be in the verb tense of loving, be in the verb tense of arguing.

We're now arguing, we're in the verb tense of reconciliation, kind of somewhere in between or something of that sort.

And how a structure and a circuit as simple as the dopamine system, right?

1 molecule could suddenly say, oh, you know what, now getting over my anger is rewarding.

Whereas 5 minutes ago, being right and being the most angry was rewarding.

And then 5 minutes before that, again, we're accelerating this movie, but 5 minutes or 5 days or 5 years before that, this person could do no wrong.

And the dopamine system is just cranking out dopamine, saying whatever you do, I'm just delighted by it.

Like to me, I can't think of a more interesting system in neuroscience.

I agree with pretty much everything you said.

I don't have much to add because what you're pointing out is 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 1 hand, you have done a fantastic job over the last few years in your podcast of making complex subjects accessible to a lay audience.

And get them to be thinking about how our modern view of how the brain works could be used to enhance health, could enhance mental wellbeing.

But as neuroscientists, academic neuroscientists ourselves, 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.

It's modified by these prefrontal inputs, which are simultaneously telling our memory systems, you know, pay attention here.

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, you know, which I never, 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?

I mean, I think for you and me, because we seem to both have, you know, like donuts, they're highly appetitive for us.

Probably doesn't matter because we have learned even a little piece of a donut activates all of our memory system saying, man, that's an old fashioned glazed donut.

I wanna eat that, or I wanna get 1, or I wanna have the discipline not to eat it.

And I'm shifting topics completely, but that's why addiction is so challenging.

Let's talk about that because you've done a ton of important work in this area of addiction.

I mean, 1 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.

We also hear that we can become addicted to anything.

When Anna Lemke was on this podcast, I said, what's the most unusual addiction you've ever seen?

And she talked about a patient who sadly committed suicide at some point later that she told us had been addicted to water, to drinking of any kind, first alcohol, but then water eventually.

And so my question about addiction in the dopamine system is, you know, let's pick a drug like cocaine.

I've never done cocaine, but people who have done cocaine tell me that it feels very good.

And 1 of the more salient features of the cocaine high is that it comes on very fast and it ends pretty quickly too.

Is the rate of dopamine increase related to the addictive property of a drug or behavior as much as how much dopamine is released?

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