How 你的 大脑’s Reward 回路 Drive 你的 Choices | Dr. Robert Malenka

这 transcript version is not in its final form 和 会 be updated.

安德鲁·休伯曼： Welcome to the Huberman Lab 播客, where 我们 discuss science 和 science-based tools 对于 everyday life.

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I'm Andrew Huberman, 和 I'm a professor of 神经生物学 和 Ophthalmology at Stanford School of Medicine. Today, my guest is Dr. Robert Malenka. Dr. Robert Malenka is a professor of Psychiatry 和 Behavioral Sciences at Stanford University School of Medicine. He is both medical doctor, an MD, 和 a researcher, a PhD. His laboratory is famous 对于 having discovered some of the key components allowing neuroplasticity, 那 is, the 神经系统's ability to change in response to experience. In addition, Dr. Malanka's 研究 is considered central to the textbook knowledge 关于 how reward 系统 in the 大脑 are organized 和 function. Indeed, Dr. Melanca's 研究 over the last ten 或 15 years has merged what was once 二 disparate fields, the 首先 being the 研究 of neuroplasticity, again, the 神经系统's ability to change in response to experience, 和 the other field being the field of 多巴胺 as it relates to pleasure 和 addiction. His laboratory has shown, 对于 instance, 那 when 我们 seek out particular forms of pleasure, regardless of whether 或 not they are healthy 对于 us, 那 changes the way 那 我们的 reward circuitry works 和 actually changes the way 那 多巴胺 is 释放了 和 how it impacts the 大脑. 和 his work has also informed how 我们 seek out healthy pleasures, including healthy food 和 social connection.

Today's discussion explores all of 这些 topics, 和 by the end of today's discussion, 你 会 have a rich understanding of how 神经化学物质 like 多巴胺 和 serotonin work in parallel, to reinforce 那 is, to 增加 the probability 那 我们 会 engage in certain types of thinking 和 behaviors. So if 你 are somebody interested in neuroplasticity, 那 is, how the 神经系统 可以 change in response to experience 和 或 你 are interested in reward 系统, what motivates us, 和 what 我们 are 可能 to pursue in the future, given 我们的 choices of past, 和 if 你 are interested in things like social connection 和 empathy, 或 lack thereof, today's discussion encompasses all of 那些 topics.

It is worth mentioning 那 Dr. Malenka is a true luminary in all of the fields I just mentioned, as well as several other fields. In fact, when 你 look out on the landscape of modern neuroscience, what 你'll discover is 那 a 非常 large percentage of the top laboratories studying neuroplasticity 和 reward 系统 和 so on, all stemmed 从 having trained in Dr. Malenka's laboratory. So it's a real honor 和 pleasure to be able to host him today, 和 I'm sure 那 我们的 discussion is going to greatly enrich the way 那 你 think 关于 大脑 function, neuroplasticity, 和 reward.

之前 我们 begin, I'd like to emphasize 那 这 podcast is separate 从 my teaching 和 研究 roles at Stanford. It is, 然而, part of my desire 和 effort to bring zero cost to consumer information 关于 science 和 science related tools to the general public. In keeping 与 那 theme, I'd like to thank the sponsors of today's podcast.

我们的 首先 sponsor is ROKA. ROKA makes eyeglasses 和 sunglasses 那 are of the absolute highest quality. The company was founded by 二 all American swimmers 从 Stanford, 和 everything 关于 ROKA eyeglasses 和 sunglasses were designed 与 表现 in 心智. I've spent a lifetime working on the biology of the visual 系统, 和 I 可以 tell 你 那 你的 visual 系统 has to contend 与 an enormous number of challenges in order 对于 你 to be able to see clearly. ROKA understands 那些 challenges 和 the biology of the visual 系统 such 那 they've designed sunglasses 和 eyeglasses 那 总是 allow 你 to see 与 crystal clarity. Now, initially, ROKA eyeglasses 和 sunglasses were designed 对于 sports 表现, 和 as a consequence, all of their glasses are designed to be 非常 lightweight 和 to not slip off 你的 face if 你 get sweaty. 然而, the design of the glasses includes some 那 are specifically 对于 sport 和 others whose aesthetic 确实 allows 你 to use them 对于 sport, as well as out to dinner 或 to work, etc. 和 那's how I use them. If 你'd like to try ROKA eyeglasses 和 sunglasses, 你 可以 go to roka.com, 那's R-O-K-A.com, 和 enter the code HUBERMAN to save 20% off 你的 首先 order. Again, 那's roka.com, 和 enter the code HUBERMAN at checkout.

Today's episode is also brought to us by 水平. 水平 is a program 那 lets 你 see how 不同的 foods 和 behaviors affect 你的 health by giving 你 real time feedback on 你的 diet using a continuous glucose monitor. 一 of the most 重要 factors impacting 你的 immediate 和 long term health is the way 那 你的 身体 manages its 血液 glucose, 或 sometimes referred to as 血液 sugar 水平, to maintain 能量 和 专注. Throughout the 天, 你 want to keep 你的 血液 glucose steady 没有 big spikes 或 dips. Using 水平, 你 可以 monitor how 不同的 types of foods 和 不同的 food combinations, as well as food timing 和 things like 运动, combine to impact 你的 血液 glucose 水平. I started using 水平 a little over a year ago, 和 it gave me a lot of insight 进入 how 具体的 foods were spiking my 血液 sugar 和 then leaving me feeling tired 对于 several 小时 afterwards, as well as how the spacing of 运动 和 my meals was impacting my overall 能量. 和 in doing so, it 确实 allowed me to optimize how I eat, what I eat, when I 运动, 和 so on, such 那 my 血液 glucose 水平 和 能量 水平 are stable throughout the 天. If 你're interested in learning 更多 关于 水平 和 trying a continuous glucose monitor yourself, go to 水平.link/huberman right now, 水平 is offering an additional 二 free months of membership. Again, 那's 水平.link L-I-N-K /huberman to get 二 free months of membership.

和 now 对于 my discussion 与 Dr. Robert Malenka. Dr. Melanka, Rob, welcome.

Robert Malenka: Yeah, thanks 对于 having me.

安德鲁·休伯曼： Delighted to have 你 here, both 对于 sake of 你的 medical knowledge 和 训练 as a psychiatrist 和 of course as a luminary in the field of neuroplasticity, 多巴胺 和 reward 系统, social 系统, 你的 knowledge of autism 和 social interactions, a newer interest in, 或 perhaps old interest in psychedelics 和 what they're doing 和 potential 对于 心理健康. There are just so many things 那 你've done in 这 field. I've been a long, longtime fan of 你的 work. Since 你的 天 as an assistant professor, I've tracked 你的 career. I've learned a tremendous amount 从 你 by observing 你 和 从 being 你的 colleague. So 确实 delighted to have 你 here.

Robert Malenka: 你're making me blush, 和 I don't blush easily.

安德鲁·休伯曼： Well, it's all true.

Robert Malenka: Thank 你.

安德鲁·休伯曼： 和 I 会 say as well, 你've also trained an enormous number of incredible scientists. Karl Deisseroth, the Karl Deisseroth, Anna Lemke 总是 speaks incredibly highly of 你 as a mentor 和 somebody she's learned a tremendous amount 从 和 pretty much anyone 那's worked on neuroplasticity, on 多巴胺 和 reward 系统, addiction, 和 now in the fields of autism 和 soon psychedelics as well, references 你 经常, 和 你've been mentioned many times 之前 on 这 podcast, if not by name, by work. So again, thank 你 对于 being here.

I'd love to kick off the conversation by talking 关于 something which is 非常 fundamental to everything 我们're going to talk 关于, 但 certainly fundamental to 我们的 daily lives, which is 多巴胺. 我们 hear so much 关于 多巴胺. 人们 talk 关于 多巴胺 hits. 人们 think 关于 多巴胺 as pleasure, 多巴胺 reward 对于 the novice. How 会 你 frame the 多巴胺 系统? I mean, it does a bunch of 不同的 things in 不同的 areas of the 大脑和身体, 但 to 你 what does 多巴胺 represent as its major function in the 大脑? 和 could 你 give us a kind of general contour of the neural 回路 那 allow 这 chemical to 更多 或 更少 put value on 我们的 experiences?

Robert Malenka: Yeah, 那's 非常 well put. As 你 point out, 多巴胺 is 一 of the major, what 我们 term neuromodulators in the 大脑, a chemical signaling messenger 那 the 大脑 uses to mediate a complex array of actions. Its best well known function is in what 我们 call the 大脑's reward circuitry. So 这 is a 回路 in the 大脑. 和 when 我们 use the term 回路, what 我们 确实 mean is 一 part of the 大脑 communicating 与 another part of the 大脑. 因为 the 大脑 is 这 非常 complex, it's the most complex organ in the universe, 与 lots of 不同的 nerve cells talking to each other simultaneously. 和 as neuroscientists, 我们 try to parse what 不同的 大脑 areas are doing 和 what 不同的 neuromodulators 可能 be doing, 和 多巴胺 was discovered, oh, I 应该 know 这, many decades ago. 和 it's, as I said, the major chemical messenger molecule in the so called 大脑's reward circuitry.

和 when 你're talking 关于, so what is the 大脑's reward circuitry? 这 is a part of the 大脑 那 tells us something is reinforcing in 我们的 environment. Some stimuli is "rewarding," makes us feel better 或 good, 尽管 那's a gross oversimplification. 之前 getting 进入 the details of 多巴胺 和 its function in the reward circuitry, I think it's useful to talk 关于, why do 我们 need a reward circuitry? Why do 我们 need something in 我们的 大脑 那 tells us, 这 feels good 或 这 feels bad, 和 it goes back to evolution. I am a biological scientist. 那 means I believe in evolution. 和 if 你 think 关于 the evolution of 我们的 species, everything is driven by developing mechanisms 那 增加 我们的 survival. 和 it's 确实 useful, 你 need something in 你的 神经系统 那 tells 你 some stimuli in 你的 environment is 重要 对于 你的 survival, 或 some stimulus in 你的 environment is dangerous.

So it's not magic 那 sugary, high fat laden foods are highly reinforcing 和 rewarding. It's not an accident. There has to be a mechanism in the 大脑 那 tells us 那. It's not an accident, 那 most of the time, 对于 most of us, a sexual experience is pretty reinforcing, is pretty rewarding. It's not an accident 那 warmth feels 确实 good when 你're 寒冷. 那 水 tastes much better when 你're 确实 thirsty. What evolved is a mechanism to tell 我们的 nervous 系统 和 tell 我们的 brains, 这 feels pretty good, I 应该 repeat the behavior 那 leads to 那 rewarding experience. 和 similarly, it's 确实 重要 when there is an event in 你的 life 那's highly dangerous 对于 some mechanism in 你的 大脑 to say, whoa, I don't want to go back to where 那 lion was. 和 我们 可以 get 进入 那.

So 这 was a long winded way of saying what the reward circuitry tells us is 这 event, 这 stimulus. It could be an external stimulus, like I said, a Krispy Kreme donut, which I happen to love. 和 I have to be 非常 disciplined, so I don't eat too many of them. It could be a drug of abuse, 和 maybe 我们'll talk 关于 那 a little bit. All of 这些 stimuli seem to activate 和 cause the 释放 of 多巴胺 in 这 大脑's reward circuitry. So now 我们 need to get 进入 a little bit of detail. Neuroscientists use 这些 非常 unfriendly terms to describe 不同的 大脑 regions. So the home of 多巴胺 cells, 或 大脑 cells, are called neurons. So the home of 多巴胺 neurons are in a part of the 大脑, sort of what 我们 call the lower midbrain. The 多巴胺 neurons 那 are part of the reward circuitry are found in 这 area called the ventral tegmental area, which, I'm sorry to have to use such technical jargon, 我们 call it the VTA. 那's the acronym.

安德鲁·休伯曼： I think the roof of the midbrain is the tectum, it means roof, 和 the base of the midbrain, it means floor, which is the tegmentum. So there's a rationale, 但 it doesn't help much at all to know the names.

Robert Malenka: 和, in fact, 你 are absolutely correct, 和 I 总是 forget 那. So thank 你 对于 pointing 那 out.

安德鲁·休伯曼： It's a side effect of teaching neuronatomy.

Robert Malenka: Which I once did back in the early 80s, 但 I've forgotten everything I taught. Anyhow, so 这些 多巴胺 neurons, 和 我们 可以 talk 关于 other types of 多巴胺 neurons, they send messages, what 我们 call projections, using telegraph wires 那 我们 call axons. They send projections to many 不同的 大脑 regions, the key 一 in the 大脑's reward circuitry being an area, again, 与 a 非常 complicated name called the nucleus accumbens, 和 maybe Andrew. 你 know, I actually don't know how 那 name evolved, the nucleus accumbens. 和 I'm sure I 应该 know, 因为 I've been studying it 对于 30 years, 但 I have 从不 looked up the genesis of 那 name.

安德鲁·休伯曼： Well, the fortunate thing 关于 这 podcast is it's both on audio platforms like Spotify 和 Apple, 但 also on YouTube. 和 so now 我们 可以 be absolutely sure 那 somebody has put it 进入 the YouTube comments underneath 这 episode, 和 因此 everyone 会 learn, including us.

Robert Malenka: So I don't know the origins of the word nucleus, 和 it's a gross oversimplification, 但 it's the activity of 这些 多巴胺 neurons in the ventral tegmental area 那 then cause the 释放 of 这 powerful neuromodulator, 多巴胺, in the nucleus accumbens, which is part of another 大脑 structure 与 a tough to remember name called the ventral striatum.

和 then magic happens, 和 when I say magic happens, even though 我们've been studying how 多巴胺 modifies the properties of cells in 这 nucleus accumbens, the truth is, 我们 don't have a deep mechanistic understanding why, when 多巴胺 is 释放了 in the nucleus accumbens, 我们 experience 那. As I'm being 非常 cautious here, the simple way 会 be to say as highly rewarding, 但 it's a little 更多 complicated than 那. What it tells us is 那 there's something 确实 重要 happening in 我们的 environment.

安德鲁·休伯曼： So could 我们 say 那 it cues the arousal 系统?

Robert Malenka: It gets the arousal 系统 going. There're close ties to 我们的 memory 系统, which hopefully, intuitively, makes some sense if something 确实 重要 is happening in 你的 environment. 因为, again, I think what's helpful 对于 你的 audience is to 总是 be thinking 关于 how 这些 系统 evolved 从 an evolutionary perspective. 和 if 多巴胺 is signaling something 确实 重要 和 salient is happening in 你的 environment, 你 want to remember 那 it could be a highly rewarding experience, like a source of food 对于 me. I like all donuts, so I don't want to emphasize any 一 manufacturer of 一 donut versus the other. I like sugar laden, fat laden foods. 那's why I 从不 eat them, 因为 I like them so much.

和 I use 那 as an example, 但 因为 那 was an 重要 event 对于 my survival. 这 reward circuitry, yes, it stimulates my arousal 系统. It gets me to pay 注意力. It also has 非常 close ties to memory 系统. 和 to go off on a little bit of a tangent, I think the 一, I don't want to say it's a mistake, I think perhaps somewhat oversimplification of how 人们 conceptualize 多巴胺's role in the 大脑 is, even though it's a major, 重要 role, is 对于 it to be active 和 释放了 期间 highly reinforcing experiences like sex, like 确实 good food, like drugs of abuse.

It also 可以 get activated, subdivisions of 这 系统, 期间 painful stimuli 和 期间 aversive stimuli, which, again, are 确实 重要 对于 你 to be aware of, to say, oh my God, 那's 确实 bad 对于 me. So the 多巴胺 系统, 这 reward circuitry 和 its subcomponents 那 maybe, perhaps signal 更多 salience 或 aversion in the environment, are closely tied to arousal 系统 和 memory 系统. Again, hopefully, 对于 somewhat obvious reasons, 你 want to remember powerfully reinforcing events in 你的 life, as well as powerfully emotionally 或 physically painful events in 你的 life. So I hope I answered 你的 question to a modest degree.

安德鲁·休伯曼： No, far better than a modest degree. 那's an excellent description of the 多巴胺 系统 从 a true expert. 和 the question I have is 关于 some of the context 和 nuance of the 系统, 但 in sort of real world terms, how 应该 I think 关于 这? Even in my 训练 as a neuroscientist, I know neurons 可以 be a little active, a lot active, everything in between. They 可以 be active over long periods of time 或 short periods of time. 但 let's use the example of the donut. I like a glazed old fashioned donut. I actually don't have a craving 对于 sweet thIngs, 但 donuts is an exception.

I like the glazed old fashioned donut, 但 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 那 更多 多巴胺 is 释放了 to the anticipation of the complete donut? 和 then the other question is, how does context influence the 多巴胺 系统? 对于 instance, if I'm 非常 full, a glazed old fashioned donut 可能 be aversive to me. Whereas if I'm just a little bit hungry, 或 if I'm actually 更多 on a schedule of rewarding myself 对于 abstaining 从 sweet, fatty foods, then abstaining 从 the food 可能 be its own form of reward.

Robert Malenka: Yeah.

安德鲁·休伯曼： 和 so, to me, the 多巴胺 系统 seems incredibly simple 和 yet incredibly prone to immediate context 和 the kinds of nuance 那 我们're constantly juggling. I'll interrupt myself to say 那 我们're constantly juggling a bunch of 不同的 reward contingencies. 我们 want to have good health metrics 和 maybe have a certain aesthetic qualities to 我们的 身体, 但 我们 also want the doughnut. 和 so how does a 系统 as simple as 一 neuromodulator 系统 和 the VTA to nucleus accumbens, 和 与 some connections to the memory area, how does it balance all of 那 information in real time? To me, 那's just, like, staggeringly complex, 但 also incredibly interesting.

Robert Malenka: I think 你,,, beautifully put, 非常 eloquent description. 你 just said it. It's staggeringly simple, simultaneously staggeringly complex. 和 你 asked several 不同的 questions. So context makes an enormous importance. 和 那's 一 of the reasons I became interested in the 多巴胺 reward circuitry is, as 你 know, as a colleague in the academic neuroscience world, 但 你的 listeners probably don't, I started out my career studying 非常 basic mechanisms of plasticity. How does the 大脑 modify itself? 和 what makes the 大脑 不同的 than the computer hardware is the physical connections in the 大脑 are constantly changing the 力量 of the communication.

Similarly 对于 the 多巴胺 reward circuitry, it's highly plastic 和 it's highly contextually dependent. 和 so 你 gave the example of donuts 和 feeding, 和 I'll answer 你的 question 关于 the cues. Yes, I used to give the example of Thanksgiving, so let me give 那 example. In the 早晨 of Thanksgiving, all, 对于 most of us in the United States, the 早晨 of Thanksgiving, if 你're at home visiting 你的 parents, the smells of the apple pie, the smells of the turkey cooking are highly repetitive, highly reinforcing. 你're anticipating 那 fun event. 你're anticipating Uncle Joe coming to visit 你 对于 Thanksgiving.

和 那's all 因为 这些 cues, the smells, the anticipation of Uncle Joe, 你的 previous experiences, are part of 你的 memory 系统, sort of talking to, in a simple way, 你的 reward circuitry. So 你're building up 这 anticipation, 一 could almost say 这 craving, which maybe 我们'll talk 关于 in the context of addiction. 和 then, make a long story short, think 关于 那 晚上 at the end of Thanksgiving. 那些 exact same cues, the exact same smell of the apple pie, turkey, 和 Uncle Joe himself. At the 非常 least, they're no longer repetitive, meaning they 可能 actually be aversive. The last thing 你 want is a piece of apple pie. 你 可以't wait 对于 Uncle Joe to leave 你的 Thanksgiving dinner. 和 I 总是 argue 那 does not happen magically.

那 happens 因为 你的 大脑 has been modified by the context in which it sits. 和 这 非常 重要 modulatory 系统, 这 reward circuitry, is responding to the exact same stimuli 与 a 非常 不同的 response. So I'm just telling 你, I'm repeating what 你 said, the phenomenology. 和 again, my other favorite example is any of us who have been in an intimate relationship knows 那 the love of 你的 life 可以 turn to the bane of 你的 existence in 20 秒. 和 again, 那 doesn't happen magically. 这 person who 你 crave, who 你 love, does something, 和 二 分钟 later, 你的 大脑 is saying, oh, my God, I may have to break up 与 这 person, 或, 这 is an incredibly painful emotional experience, 和 what fascinates me 关于 the 大脑 is, how does the 大脑 mediate 那 rapid change?

So now back to, so, yes, context is everything 关于 how 这 powerful neuromodule choice 系统 那 uses 多巴胺 works, 和 the truth is, 我们 don't know. It's 因为 the inputs onto 这些 多巴胺 neurons, the other nerve cells 那 are driving the activity of the 多巴胺 neurons, 和 I've actually studied 这 in my lab at Stanford University 与 a colleague 你 know well, Lee Chun Luo, who's a world class neuroscientist. 我们've studied the complexity of the neuroanatomy of the 多巴胺 系统, 和 这些 多巴胺 neurons in the ventral tegmental area, the source of the reward circuitry, 多巴胺, are receiving inputs 从 all over the 大脑. They're receiving indirectly 或 directly inputs 从 visual areas, 从 somatosensory areas. 和 I'm not giving 你 a 确实 good answer 因为 那's 一 of the goals of my 研究, to try to understand how context, how the history 那 你've had 与 这些 cues, which 我们're going to get back to of the donut 或 of a drug, how has 那 modified how 这 neuromodulatory 系统 responds?

Similarly, the nucleus accumbens, the target of 这 powerful modulator, 多巴胺, is receiving communications, what 我们 call inputs 从 all sorts of 大脑 regions 那 你 know 关于. Andrew, 你的 audience may not. It receives inputs 从 an area called the hippocampus, which 你 may have covered in previous podcasts, which is 非常 powerfully, 非常 重要 对于 memories, both establishing new memories 和, again, remember, 那 makes sense. 你 want 这 系统, 这 多巴胺 reward circuitry, to be 非常 connected to memory 系统. So the activity in the nucleus accumbens is modulated by 多巴胺 while it is receiving information 从 the hippocampus, which helps encode new memories, while it's receiving information 从 a 大脑 area called the amygdala, which is a part of the 大脑 involved in 我们的 emotional experiences. The accumbens also receives inputs 从 the prefrontal cortex, which is 这 大脑 area. As 你 know better than me, Andrew, is 重要 对于 decision making, 对于 planning 我们的 activity, 和 I could go on 和 on.

安德鲁·休伯曼： Well, could 我们 talk 关于 prefrontal cortex 对于 a moment, 因为 it 总是 was surprising to me 那 prefrontal cortex is talked 关于 as 这 higher executive function area. 但 then when 你 look at the neuroanatomy, it's, as 我们 say, monosynaptically, as 你 和 I know, 一 connection away 从 structures like the amygdala, 一 connection away 从 structures like the nucleus accumbens. In other words, prefrontal cortex, to me, is every bit as ancient as some of 这些 other structures 那 我们 think of as 更多 ancient, 和 确实, the whole ancient evolved thing gets a little bit dicey 因为 certain areas aren't like the prefrontal cortex, are 更多 elaborated in humans.

但 to me, the prefrontal cortex seems to be 尤其是 重要 in the context of 这 thing of scaling the reward response, 或 context of the reward response, 因为 it 可以 set rules. It seems to know, okay, 我们're recording a podcast now, 和 there are certain rules, there are certain things 那 我们're going to do 和 not do. 但 what's fascinating 关于 the, 和 I'm so glad 你 gave a bunch of 不同的 examples, 因为 what's fascinating, 对于 instance, 关于 the relationship example is 那, yes, at 一 moment 我们 可以 adore somebody, 和 another moment later, if they do something 或 don't do something, 我们 可以 be incredibly frustrated 与 them. They 可以 even become aversive to us. Hopefully, 那 doesn't happen too frequently.

Robert Malenka: Hopefully.

安德鲁·休伯曼： 但 I think 我们've all had the experience of a doughnut, an event, 或 a person actually looking 不同的 to us 从 一 moment to the next, hopefully not at random. 和 so, to me, it seems like the prefrontal cortex is uniquely positioned to 确实 say, okay, right now 我们 are in a mode of, 对于 lack of a better word, love 和 loving, like in the verb tense of loving, be in the verb tense of arguing. 我们're now arguing. 我们're in the verb tense of reconciliation, kind of somewhere in between 或 something of 那 sort, 和 how a structure in a 回路 as simple as the 多巴胺 系统, 一 molecule could suddenly say, oh, 你 know what? Now getting over my anger is rewarding. Whereas five 分钟 ago, being right 和 being the most angry was rewarding, 和 then five 分钟 之前 那, again, 我们're accelerating 这 movie, 但 five 分钟 或 five 天 或 five years 之前 那, 这 person could do no wrong, 和 the 多巴胺 系统 is just cranking out 多巴胺, saying, whatever 你 do, I'm just delighted by it. Incredible. Like, to me, I 可以't think of a 更多 interesting 系统 in neuroscience.

Robert Malenka: Well, I mean, 那 was eloquently put. I agree 与 pretty much everything 你 said. I don't have much to add, 因为 what 你're pointing out is the challenges of studying 这些 系统, the importance of studying 这些 系统, 和 the challenge of presenting how the 大脑 works to 这 podcast audience. 因为 on the 一 hand, 你 have done a fantastic job over the last few years in 你的 podcast of making complex 受试者 accessible to a lay audience 和 get them to be thinking 关于 how 我们的 modern view of how the 大脑 works could be used to 增强 health, could 增强 mental well being. 但 as neuroscientists, academic neuroscientists ourselves, 我们 know, 你 know, 你 are oversimplifying things, 和 the actual functioning of a 系统 like the 多巴胺 reward circuitry, as 你 just eloquently pointed out, is so much 更多 complex. It's modified by 这些 prefrontal inputs, which are simultaneously telling 我们的 memory 系统, pay 注意力 here. I'm repeating what 你 just said.

The context makes a big difference, the history 你 have 与 the person 或 stimuli 与 whom 你're interacting. Like to bring 这 back to 你的 which I 从不 - the initial question - does a small piece of a doughnut activate the cue 那, 那 small piece of a donut activate the reward circuitry 和 cause 释放 of 多巴胺 to the same extent as the full donut? Depends on 你的 experience 与 donuts. I think 对于 你 和 me, 因为 我们 seem to both like donuts, they're highly repetitive 对于 us, probably doesn't matter, 因为 我们 have learned even a little piece of a doughnut activates all of 我们的 memory 系统, saying, man, 那's an old fashioned glazed donut. I want to eat 那. I want to get 一, 或 I want to have the discipline not to eat it. So I hope I'm answering 你的 question, 和 I'm shifting topics completely. 但 那's why addiction is so challenging. Well, let's talk 关于 那.

安德鲁·休伯曼： Let's talk 关于 那, 因为 你've done a ton of 重要 work in 这 area of addiction. I mean, 一 of the basic questions I have 关于 addiction know 我们 hear 那 certain drugs are 更多 addicting than other drugs 或 certain behaviors. 我们 also hear 那 我们 可以 become addicted to anything. When Anna Lemke was on 这 podcast, I said, what's the most unusual addiction 你've ever seen? 和 she talked 关于 a patient who sadly committed suicide at some point later 那 she told us had been addicted to 水, to drinking of any kind, 首先 alcohol, 但 then 水 eventually. So my question 关于 addiction in the 多巴胺 系统 is, let's pick a drug like cocaine. I've 从不 done cocaine, 但 人们 who have done cocaine tell me 那 it feels 非常 good. 和 一 of the 更多 salient features of the cocaine high is 那 it comes on 非常 fast, 和 it ends pretty quickly, too. Is the rate of 多巴胺 增加 related to the addictive property of a drug 或 behavior as much as how much 多巴胺 is 释放了?

Robert Malenka: 和 那's a 非常 sophisticated question, 和 the answer is yes. 和 那's usually the lecture I give, the way I think 关于 addiction, 和 obviously my friend 和 colleague Anna Lemke is 一 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 多巴胺 neurons act, 和 the way, like any, what appears to be a simple term, it's layered 与 complexity. Addiction is somewhat of a continuum. 和 I like to think 关于 whether 你're talking 关于 substances like cocaine, 和 I 会 explicitly answer 你的 question soon, 或 opioids. As 你 know, 我们're going in 这 country, there is an opioid epidemic. I do like to think 关于 addictive liability, 和 in my view, it is pretty clear 那 when 我们're talking 关于 drugs, they have 不同的 degrees of addictive liability.

I mean, I had a cup of coffee 这 早晨, 和 many of us listening to 这 podcast, it's 确实 hard to start 我们的 天 没有 getting 那 hit of caffeine. 但 are 我们 addicted to caffeine? 那's a tricky question, 因为 I've 从不 heard of anybody robbing a bank to get caffeine, destroying their personal life to get caffeine. So I 会 say caffeine causes tolerance, 但 I 会 not say it has a particularly high addictive liability, whereas drugs like psychosimulants, like cocaine 或 opioids, have a 非常 high addictive liability. So, to answer 你的 mechanistic question, there have been some famous 研究 done by the director of the National Institute on Drug Abuse, Nora Volkow. Simultaneously, there have been 研究 in animal models of addiction where 你 nailed it.

In a rough way, the addictive liability of a substance is directly correlated 与 二 aspects of 多巴胺. How much 多巴胺 is 释放了 in the accumbens 和 the kinetics of the 多巴胺 释放. As 你 said, how rapidly it's 释放了. To get a little technical, even 与 a drug like cocaine 或 opioids, it's not only the drug itself, it's the route of administration, 因为 the root of administration influences the kinetics, meaning how fast 那 drug gets 进入 你的 大脑 influences the reward circuitry 和 how fast it causes a big, rapid 释放 of 多巴胺. 和 some of 你的 podcast listeners may be old enough to remember the crack cocaine epidemic 或 free base cocaine. 和 cocaine does have, like methamphetamine, a 非常 high addictive liability. I give lectures to students at Stanford 关于 神经生物学 of addiction as part of a team taught course. I have kids who I had to deal 与, 和 what I 总是 say is, it's not 那 if 你 use 这 drug, 你're automatically going to become an addict, 但 你're taking 那 risk. 和 it is impossible to become addicted to a substance if 你've 从不 used it, by definition, 但 back to the root of administration. So I went off--

安德鲁·休伯曼： --那's actually an interesting statement, 因为 I think 我们 may have heard 那 in high school, 尽管 I, to be honest, wasn't the most attentive high school student, 和 I regret 那 high school students, pay 注意力!

Robert Malenka: 你 did okay 对于 yourself. [LAUGHS]

安德鲁·休伯曼： Eventually I came 大约, 但 it was an uphill battle. 但 那 你 可以't become addicted to something 那 你've 从不 done, which I just want to earmark 那 因为 I think it's a profound statement, 因为 it points to the importance of the memory 系统, 但 also plasticity. 和 so I want to make sure 那 eventually 我们 get 大约 to talking 关于 how the amount of 多巴胺 释放了 和 the kinetics, how 那 可能 influence plasticity.

Robert Malenka: Absolutely.

安德鲁·休伯曼： What I'm asking here, queuing up in the back of 你的 心智, is whether 或 not addiction is just related to the sensation 那 我们 have when 我们 indulge in a behavior, 或 when 我们 are under the influence of a drug, 或 whether 或 not it actually modifies neural circuitry in a way 那 makes a broader range of drugs 或 experiences attractive to us.

Robert Malenka: It's probably the latter, 但. So let me get back, 和 I 会 answer 那 in a 秒 to the point I was making. So it's not only the substance, it's the route of administration. As I said, 你 可以't develop a problem 与 a substance 和 develop a substance abuse problem if 你 从不 take it. 但 snorting cocaine is a 不同的 experience than smoking it 或 injecting it. 和 一 of the reasons the crack cocaine epidemic was so powerful, is it gets 进入 when 你're smoking it 或 injecting it. 和 人们 do 这 now 与 methamphetamine, I mean, meth addicts, most of them. 和 那 is another epidemic in 我们的 country. Most of them smoke it. 和 the danger of 那 is the drug, whether it's cocaine, methamphetamine, gets 进入 你的 大脑 almost instantaneously, causes a 非常 rapid, powerful surge of 多巴胺 in the accumbens in 这 reward circuitry.

和 那 the feeling 你 get, which, 和 我们're going to get 进入 这, is not necessarily a happy feeling, 和 it 可以 last 对于 tens of 秒 或 a few 分钟, 和 it's a feeling 那 gives 你 这 overwhelming compulsion 和 urge, I want to do it again. Even though it may not actually feel all 那 good, 和 again, 这 gets 进入 我们 didn't have an addiction problem 对于 any substance other than alcohol, 对于 most of humanity's existence, 因为 这些 substances like cocaine, methamphetamine, synthetic opioids like fentanyl, they didn't exist. 和 the truth is, 我们的 brains are not designed to handle 那些 kinds of 非常 powerful substances.

安德鲁·休伯曼： As many of 你 know, I've been taking AG1 daily since 2012. So I'm delighted 那 they're sponsoring the podcast. AG1 is a vitamin mineral probiotic drink 那's designed to meet all of 你的 foundational nutrition needs. Now, of course, I try to get enough servings of vitamins 和 minerals 通过 whole food sources 那 include vegetables 和 fruits every 天. 但 oftentimes I simply 可以't get enough servings. 但 与 AG1, I'm sure to get enough vitamins 和 minerals 和 the probiotics 那 I need. 和 it also contains adaptogens to help buffer 压力. Simply put, I 总是 feel better when I take AG1. I have 更多 专注 和 能量 和 I sleep better. 和 it also happens to taste great. 对于 all 这些 reasons, whenever I'm asked if 你 could take just 一 supplement, what 会 it be? I answer AG1. If 你'd like to try AG1, go to drinkag1.com/huberman to claim a special offer. They'll give 你 five free travel packs plus a year's supply of Vitamin D3K2 again, 那's drinkag1.com/huberman.

Robert Malenka: So, where do 你 want to go 从 here? 你 asked a question 关于 the neural mechanisms of what 我们 call addiction.

安德鲁·休伯曼： Yeah, I'd like to know 关于 the role of neuroplasticity 和 addiction. I do want to highlight something 你 said, 和 I apologize 对于 interrupting a moment ago. 和 then I refrained, 但 it was an interruption based on real excitement 因为 a person I know quite well, who is a recovered cocaine addict, told me. 和 那, by the way, folks, 这 isn't, I have a friend 和 I'm actually, 你 know... I truly have 从不 tried cocaine. 和 这 person said 那 the 首先 time they did cocaine, his thought was, I hate 这, 和 I 可以't wait to do it again. 和 那's exactly how 你 described it.

Robert Malenka: 和 I think 那 is a fairly common experience 与 人们 suffering 从 an addiction disorder. 我们're not supposed to use the word addicts anymore 因为 那's a little bit judgmental.

安德鲁·休伯曼： 那's the new nomenclature.

Robert Malenka: Something along 那些 lines.

安德鲁·休伯曼： Got it. Calling someone an addict as opposed to being addicted.

Robert Malenka: Yeah, being. 和 那 is a beautiful description. I hate it, 但 I want to do it again 和 again. It just shows the power of 这 系统, which, remember, evolved 对于 我们的 survival. So a 非常 simple way of thinking 关于 it is 这些 drugs are tricking the reward circuitry to say, 这 stimulus, 这 experience, is 确实 重要 对于 my survival. I have to go do it again 和 again 和 again. A side question is, the huge question is, why do some 人们 develop an addiction problem 和 others who have used 这 substance just don't? 和 again, as a world class neuroscientist yourself, 你 know the answer. It's 总是 a complex combination of underlying genetics, the environment in which they find themselves, the environment in which they grew up, 和 how 那 modified their reward circuitry.

So, to get at 你的 question, 一 set of experiments my lab did, which other labs did, too, I don't deserve the sole credit 对于 这, is showing 那 drugs of abuse cause powerful plasticity in the neurons 那 make up the cells 那 make up the reward circuitry. 和 in fact, drugs of abuse, like cocaine, methamphetamine, opioids like morphine, heroin, change the synapses. The synapses are the connections 从 other nerve cells onto 多巴胺 neurons, onto the nerve cells 和 the accumbens. 和 这些 connections, 这些 synapses, 可以 change. 和 drugs of abuse cause powerful changes in 那些 connections, 和 因此, powerful changes in the activity of the 多巴胺 neurons 和 the neurons in the nucleus accumbens.

和, in fact, the types of changes 那 occur appear to be 相似的 to the types of changes 那 have evolved 对于 good uses 对于 adaptive forms of learning 和 memory. So, again, 这 is an example 那 这 superficially simple 多巴胺 reward circuitry is changing all the time, 和 it's highly plastic 和 可以 become 更多 sensitive to certain experiences, etc, etc.

安德鲁·休伯曼： Well, could I ask a question 关于 some of the general contours of the plasticity 和 the 多巴胺 系统? 你 said 之前, 和 I love 这 statement, even though it's 非常 simple, 但 in its simplicity, it's 确实 elegant 那 我们 可以't become addicted to a substance 或 a behavior 那 我们 haven't taken 或 partaken in. So is there 数据 to support the idea 那 just 一 exposure to cocaine 或 一 exposure to some sort of behavior 可以 lead to a lasting change in the 多巴胺 系统, such 那 一's propensity to be addicted to 那 substance again, if 一 were to indulge in the future, 或 behavior again in the future, is 增加了? 和 I have a 非常 particular reason 对于 asking 这, 但 I'm 非常 curious what the answer is.

Robert Malenka: I mean, in the work my lab 和 other labs have done in preclinical rodent models, the answer is yes. A single administration of a drug of abuse, like cocaine, like morphine, 可以 cause relatively several 天, several 周 of changes in the connections onto 多巴胺 neurons 和 onto the neurons in the nucleus accumbens 那些 changes. 那 does not mean 这些 changes are permanent 或 irreversible, 但 the changes last a long time. 和 again, the big question 对于 understanding the 神经生物学 of addiction is, 那些 changes are probably happening in most 人们 who take the drug. In 这 case, 和 我们 可以 talk 关于 other stimuli, non drug stimuli 那 可以 become "addictive."

Again, why in certain 个体? To be honest, it's not a big deal. Yeah, I did cocaine at 这 party. It was nice, 但 I don't feel any craving 或 urge to do it again. Whereas other 个体, it sets them down a 非常 bad path 和 确实 badly affects their life. 和 那's a huge question in the 研究 field, 因为 obviously, if 我们 could make predictions on which 个体 are 更多 susceptible, 和 not to get too political here, 但 whether 你 become, develop a problem 与 addiction, 或 not is influenced by the other parts of 你的 life. Do 你 have other ways of getting, reinforcing stimuli, getting satisfaction, having an outlet, 那 other ways of activating 你的 reward 或 多巴胺 circuitry? Healthy ways, right? Like, as 你 have articulated, I think, in 你的 podcast, getting 运动. 你 和 I both like to get 运动. I feel 确实 good. Sometimes it's painful 期间 the 运动, 但 afterwards I feel great.

安德鲁·休伯曼： Almost the inverse of the cocaine response.

Robert Malenka: Yeah, the desire.

安德鲁·休伯曼： 和 then I hate 这, 但 I 可以't wait to do it again. It seems like 运动 is 经常 the opposite. I hate 这, I don't want to do 这. 和 then afterwards, gosh, I 总是 feel better 和 I'd be happy to do it again.

Robert Malenka: Yes, I like to 运动 chasing a ball, 因为 那 gets me off thinking 关于 这 hurts anyhow, back to addiction. So, yes, 这些 drugs 可以 cause, I don't want to, definitely not permanent, changes 从 a single exposure. 和 the types of 研究 I'm talking 关于 were all done in experimental animals. So how 那 relates to what happens in 我们的 brains, in human 受试者 brains is not completely clear, 但 I think there are parallels. So the changes 可能 last a few 天, a 周 或 二, 但 一 可以 see if somebody, there have been 研究 done where, in an animal model, if 你 give repeated administration of a drug like cocaine, the changes get stronger 和 they last longer, which is kind of intuitively obvious.

但 again, the big question is why, in human 受试者, there are 人们 who 可以 use 这些 substances 和 not develop a serious problem, 和 there are others where they're 非常 damaging. 和 then 那's why I still make the point. If 你're a young person, do 你 want to take 那 risk? Is it worth it to have 那 experience? 和 那's an individual decision.

安德鲁·休伯曼： 我们've done some podcast episodes 关于 alcohol, cannabis, etc., 和 there just seem to be a pretty wide variation in 人们's response to the information, I think 因为 there are 人们 out there who, well, I've got friends who are recovered alcoholics who 会 tell me the 首先 drink they took, they use language like it combined 与 the chemistry of my 身体 in a way 那 nothing 之前 ever had. 和 they felt like it was like 这 magic elixir, right? 那 has not been my experience.

Robert Malenka: I have heard the same stories, 和 it's hard 对于 me to relate, 因为, like 你, alcohol does not have 那 effect on me. 和 it's hard to believe 那 kind of immediate response to alcohol is due to the environment in which they grew up, 尽管 那 可以 have an influence 那 just feels almost 更多 genetically encoded. 和 there is 证据 那 issues 与 the use of alcohol 和 developing alcohol use disorder does run in families. 和 obviously, if it runs in family, 你 have to worry 关于 how the environment of 那 family influences it. 但 there's a lot of 研究 saying there is a genetic component. Maybe, like 你, if I have a drink 或 二 in the 下午, I just fall asleep, 和 it does not have 那 effect on me. 和 anyone 可以 imagine 相似的 things 对于 other drugs of abuse. There are 人们 who have used cocaine, have used methamphetamine, who find it modestly enjoyable, 但 it's not the be all 或 end all, isn't 这 incredibly powerful experience. 和 你 just talked 关于, I think, a friend 或 a colleague who said, I hate it. I hate 那, 但 I want to do it again. 和 那's fascinating.

安德鲁·休伯曼： Yeah. They're now a recovered alcoholic 和 cocaine addict, 和 they've abstained 对于 many years, 但 still get a little bit of a gleam in their eye when they talk 关于 alcohol 或 cocaine in a way 那 I just 可以't relate to.

Robert Malenka: 可以 I tell 你 a little vignette 关于 me? Which I love to tell.

安德鲁·休伯曼： Sure.

Robert Malenka: 和 it gets 进入 how the reward circuitry is so closely associated 与 memory 系统 和 how cues associate it 与 powerful experiences, develop their own reinforcing 或 aversive quality. So, long story short, when I was a young kid, I 可以't remember in my 20s, maybe 20, I spent a few 周 in Paris, I started smoking cigarettes. I mean, 这 is a long time ago, 和 cigarettes are 非常 interesting. Nicotine is highly addictive, as the tobacco companies were fully aware of.

安德鲁·休伯曼： High addictive liability.

Robert Malenka: 非常 high addictive liability.

安德鲁·休伯曼： 人们 会 rob 人们 对于 the money to buy cigarettes.

Robert Malenka: They may not rob 因为, 尽管 my understanding is they've become quite expensive, 但 counterfeit cigarettes are a huge market 对于 organized crime. There are parts in the world, third World countries, where organized crime produce counterfeit cigarettes 和 are making hundreds of millions 或 billions of dollars. I think nicotine as it is delivered in cigarettes, as 你 know, I mean, tobacco companies put in a lot of work to figure out the exact dose of nicotine 那 会 make 你 get 那 kind of feeling 那 only lasts 对于 a few 分钟, so 你 want to do it again 和 again.

So 我们 可以 talk 关于 nicotine. What becomes a problem in a 具体的 society 与 addiction is not only based on the neurobiological actions. If 我们're talking still 关于 drugs 或 substances of 那 substance, it's heavily influenced by the availability of the substance. 但 my little story is, I smoked some cigarettes in Paris. I learned why 人们 like to smoke. It was 非常 satisfying to have a cigarette in a Parisian cafe. 和 it's 非常 interesting 因为 the 首先 few times 你 inhale tobacco, 你 get dizzy. It's kind of aversive, 和 it's exactly what 你 articulated. Despite 那, 你 want to do it again. So it was just a lot of fun 对于 me. I enjoyed it, 和 I was disciplined. At some point, whenever 这 was, I came back to the United States. I didn't smoke 因为 I knew it was bad 对于 你.

但 to 这 天, 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 have 那 feeling again of inhaling the smoke. 但 the point is of how powerful 这些 rewarding experiences 可以 be, 或 reinforcing experiences. 和 对于 你的 audience, technically, what I have been taught by some of my psychology colleagues is 我们 use the term reinforcing in a 非常 behaviorally defined way. Something is reinforcing is if the behavior 那 led to 那 stimuli, it makes 你 want to do 那 behavior. Again, rewarding means it actually felt "good."

安德鲁·休伯曼： 那's an 重要 distinction.

Robert Malenka: They actually 可以 be 不同的. Again, as 你 defined by 你的 friend who his, I forget, I think it was cocaine. Cocaine was highly reinforcing, 但 it was not necessarily enjoyable 或 rewarding. 和 isn't 那 fascinating? I have some colleagues in the addiction field. 一 of them is retired now, Kent Barridge 和 Terry Robinson. They distinguish between the terms wanting 和 liking. 和 think 关于 那. Liking something means it's something 你 like, 你 enjoy. Wanting means 你 want it, 但 你 don't necessarily like it 或 enjoy it. 和 那's a description of 你的 friend's experience 与 cocaine. Some of us have been in destructive relationships where 你 want 那 individual, 但 你're not sure 你 necessarily like 那 individual.

安德鲁·休伯曼： Sometimes 人们 会 be in relationships where they actively dislike the other person, which is a bit foreign of a concept to me, 但, well, it's interesting. 这 separation of reinforcing 和 rewarding wanting 和 liking, 因为 一 of the things 那's 非常 prominent in twelve step programs is to create rewards 大约 abstaining 从 the drug 或 behavior. 和 I 应该 mention 那 programs like twelve step, when followed, seem to have 非常 high success rates. At least 那's what Ana Lemke tells me, 那 in some ways they are modifying the wanting 和 liking. They're splitting the wanting 和 liking of alcohol, 对于 instance, creating a liking of sobriety 更多 than the wanting of alcohol, 对于 instance.

Robert Malenka: 那's beautifully put. 和 I think 那's right. How 那 plays out in the neural mechanisms 那, as a neuroscientist, I'm interested. Man, 那's a tough 一, 但 I think 那's why 那些 programs are pretty successful. It's helping the person make 那些 dissociations. 和 I don't know 那 much 关于 那些 programs 因为 I have not seen patients myself 对于 whatever it's been, 27, 28 years. 但 I think part of them are to help 那 individual find, both other sources of liking 和 reward, getting some satisfaction 和 reward 从 the actual abstinence, being able to cognitively teach themselves 那 I deserve a pat on the back. I deserve credit. I feel good 那 I did not take a drink at 那 party 那 I did not use 那 substance again. 和 how 那 plays out in 我们的 brains is a 确实 tough 一.

安德鲁·休伯曼： Yeah, the way 你 described it is exactly right. 那些 programs are highly reinforcing 对于 abstinence behaviors, everything 从 the social connection, which 我们're going to get to social connection, as 你 know, to the way 那 人们 start to conceptualize their addict self versus other self. It actually involves a splitting of the self in interesting ways. As long as 我们're talking 关于 donuts, cigarettes, alcohol, cocaine. I'm curious, 之前 我们 move to a bit 更多 on neuroplasticity, is there anything 那 人们 ought to know 关于 how 不同的 substances 和 behaviors 那 are addicting 可能 impact the 多巴胺 reward circuitry differently?

So, 对于 instance, 我们 talked 关于 cocaine as having 这 非常 rapid onset, big 增加 in 多巴胺, then a crash, as 我们 know, a certain pattern of kinetics, as 你 describe it, the opioid crisis is incredibly serious problem right now, as is methamphetamine. 但 it sounds like methamphetamine functions a bit like cocaine. 和 in terms of its kinetics, yes. So an opioid is a 非常 不同的 chemical than cocaine, 但 it sounds like it impacts the 多巴胺 系统. Is the 多巴胺能的 activity caused by opioids responsible 对于 the addictive properties of opioids? 或 do 人们 also like the feeling of being under opioids? I personally hate it coming out of surgery. Like, they gave me Vicodin once 和 I hated it. I'd rather have the pain, the postoperative pain, than take something like Vicodin 或 a Valium 或 fentanyl 或 anything like 那, to me, is just completely aversive. 但 I realize 那 there are many millions of 人们 那 feel quite differently.

Robert Malenka: It's a great question. So I think all the 研究, both in human beings 和 preclinical animal models, yes, 会 suggest 那 the addictive liability of opioids 和 psychostimulants, which are cocaine 和 methamphetamine, have the common final action of causing massive 释放 of 多巴胺 in 这 target of the 多巴胺 neurons, the nucleus accumbens. They do it, if 我们 want to get a little scientifically technical here, via 非常 不同的 mechanisms. So cocaine 和 methamphetamine, what the drugs known as psychostimulants, actually bind to a protein in the 大脑, 或 a molecule in the 大脑 那 is responsible 对于 sucking up. It's a vacuum cleaner sucking up the 多巴胺 之后 it's been 释放了. 和 cocaine prevents 那 多巴胺 从 being vacuumed up. So the cocaine hangs 大约 longer. Meth not only prevents the 多巴胺 从 being vacuumed up, it actually causes the reverse. It actually causes the direct 释放 of 多巴胺 从 what 我们 call nerve terminals, 从 the site where 多巴胺 is 释放了.

Opioids work 非常 differently. They actually primarily, not solely work where the 多巴胺 neurons live. 和 it's a little complicated, it's not 那 critical, 但 they indirectly 增加 the activity within the 多巴胺 neurons themselves, causing a big, massive, bigger than normal 释放 of 多巴胺. So 那's 一 commonality. 但 anybody who has used 这些 drugs 或 read 关于 这些 drugs, the subjective experience of the drugs are dramatically 不同的, 和 那's 因为 of the actions they're having, not only in the reward circuitry, 但 throughout the 大脑.

和 it's interesting, 你 talked 关于 Vicodin. I've taken Vicodin 因为 I've had several knee surgeries 和 things. Like 你, I didn't like it. I've gotten other opioids 对于 pain relief 那 were great. I mean, they took away a lot of pain 之后 my ligament repair. 和 那's a 不同的 question, 那 even when 你're talking 关于 opioids, all drugs, they're not identical. Fentanyl has a much big, larger addictive liability 因为 of its molecular properties 和 how it's interacting 与 the opioid 系统 in 我们的 brains 和 the 受体, the actual proteins in the 大脑 那 it interacts 与.

但 the subjective experience of opioids, it's interesting. Some 人们 love it. If 我们 go back in history, as 你 know, there were the opium dens throughout Asia. There were wars 关于 opioids, the famous opioid wars between China 和 the United Kingdom, showing 你 how powerful the availability of a substance like an opioid 可以 be. So I'm going off on a tangent.

安德鲁·休伯曼： No, I think 这些 are 重要.

Robert Malenka: 但 commonality is 多巴胺 释放 in the, if 你 remember what a ven diagram is, 这些 drugs have some common actions, usually on, directly 或 indirectly, causing the massive 释放 of 多巴胺 in the accumbens. 但 then they have their own individual actions, 因为 obviously, when 你 take cocaine 或 methamphetamine, it's a stimulator. 人们 are grinding their teeth, they're hyped up. 对于 most 人们, opioids are the exact opposite in opium dens. 从 the movies I watched 和 watching narcos 和 all 那些 TV shows, 你're lying down, 你're kind of in almost a dreamlike state. So 非常 不同的 subjective experiences.

安德鲁·休伯曼： I'd like to just take a brief break 和 thank 一 of 我们的 sponsors, which is LMNT. LMNT is an electrolyte drink 那 has everything 你 need 和 nothing 你 don't. 那 means plenty of salt, sodium, magnesium 和 potassium, the so called electrolytes, 和 no sugar. Now, salt, magnesium 和 potassium are critical to the function of all the cells in 你的 身体, in particular to the function of 你的 nerve cells, also called neurons. 和 我们 now know 那 even slight reductions in electrolyte concentrations 或 dehydration of the 身体 可以 lead to deficits in cognitive 和 身体表现. LMNT contains a science backed electrolyte ratio of 1000 milligrams. 那's 1 gram of sodium, 200 milligrams of potassium 和 60 milligrams of magnesium.

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Yeah, I had an experience 与 an opioid recently, not voluntarily. Over the Christmas holiday, 我们 went to visit friends, 和 之前 going to sleep, I wanted some tea, 和 I asked if they had any non-caffeinated tea. So they gave me 这 tea. 和 那 夜间 I had the most bizarre dreams I've ever had. 和 I slept 对于 14 小时. The next 早晨, I was like, what was 那 tea? 和 I felt off in the 早晨. 和 it was actually a blue lotus flower tea 那 is actually illegal in the United States, 但 it is sold 和 it has morphine like compounds in it. 和 I am 一 of 那些 人们 那's 非常 susceptible to even low doses of any kind of novel drug.

Robert Malenka: Interesting. Have 你 ever taken cough syrup 与 dextromethorphan?

安德鲁·休伯曼： No, I avoid 那 stuff.

Robert Malenka: Well, I have a tendency when I get a 寒冷, it gets 进入 my lungs. I cough a lot. 和 I think 这 has been reported. 这 is my anecdotal experience. I'm confirming what 你 said. Dextromethorphan is a 不同的 sort of opioid. 和 actually, some 人们 develop a problem 与 it, 对于 me, it gives me 确实 bizarre dreams. 确实 相似的 to what 你 were describing.

安德鲁·休伯曼： It was 非常 unusual.

Robert Malenka: 和 那's a whole 不同的 conversation 关于 what makes us dream 和 what are the meaning of dreams. Fascinating. I hope 你 covered. Maybe 你've covered 那.

安德鲁·休伯曼： 我们 have. Not yet, 但 我们 are intending to do a whole series on sleep 和 dreaming, 和 我们'll definitely get 进入 it.

Robert Malenka: I started out in sleep 研究, so I have a fondness 对于 it.

安德鲁·休伯曼： Well, drug 研究 和 sleep 研究 have a long history of overlap 与 Alan Hobson's work on--

Robert Malenka: --I worked 与 Alan Hobson.

安德鲁·休伯曼： Okay, by the way, folks, if 你're interested in the relationship between hallucinations 和 dreaming, Alan Hobson is a good name to start 你的 rabbit hole.

Robert Malenka: Oh, my God. I'm dating myself. I 可以't remember if it was '76 或 '77, I worked 与 Alan Hobson as an undergraduate--

--At Harvard Medical School--

--No, as an undergraduate at Harvard. He was at Harvard Medical School. Yeah.

安德鲁·休伯曼： Amazing. I love his writing, 和 I learned a lot 从 it. He was 确实 ahead of his time.

Robert Malenka: Yes, he was. Anybody who knows me won't believe 这, 但 back then, I was a 非常 shy, insecure 20 year old--

安德鲁·休伯曼： --I 会 not have guessed--

Robert Malenka: --who, even in medical school, I literally was not confident of my opinions at all. I was 非常 shy, thought all of the ideas I had must be obvious 那 I 应该 从不 say them out loud.

安德鲁·休伯曼： Do 你 心智 if I ask, since 你 raised 这, I think it's 确实 重要. I mean, 你 have 这 incredible career track record. 你're adored by 你的 colleagues, 你're highly respected, 你've won just 关于 every award there is to winning neuroscience. So was there something in particular 那, was it an overnight thing where 一 天 你 woke up 和 thought, I actually believe in myself? 但 if 你 wouldn't 心智 sharing 那, 因为 I think 之前 我们 get back 进入 some of the science. Science is a human endeavor, 和 most 人们 listening are probably not scientists, 但 I think everybody deals 与 这些 issues of self-doubt, 和 人们 appear to have varying 水平 of confidence. 但 what happened?

Robert Malenka: Thank 你 对于 asking. 对于 me, it was a 非常 gradual process. 和 as an undergraduate, as a medical student, even as a postdoc, yeah, I was 非常 unsure of my ideas, of my intellectual abilities, of whether what I was thinking was 确实 worthwhile. So it was a 非常 gradual process, I think. The 增加 in my confidence, I think, began when I was a postdoc, which is a 训练 period 之后 你've received a PhD 或 an MD, where 你 get additional 研究 训练. 和 I worked 与 a guy named Roger Nicoll at UCSF, 和 Roger was a 非常 intellectually intense, 非常 forceful individual. 和 I got involved in a field where, I mean, 人们, a little bit of a tangent, 你的 listeners may think 那 scientists are 这些 geeky 个体 wearing white coats 与 no passion 或 emotion, 和 nothing could be further 从 the truth. The most successful scientists I know are pretty passionate 和 pretty intense 关于 what they're working on 和 driven. 和 这 is a gross generalization.

So, anyhow, 期间 my postdoc, I started getting involved in a topic where there were vigorous arguments 关于 phenomenology 我们 were studying. So I had to develop a tougher 和 thicker 皮肤. I had to be able to argue my side of the hypotheses 我们 were generating. So it started developing as a postdoc, 和 then it slowly evolved. As an assistant professor, 和 对于 你的 listeners who don't know, I don't like to admit 这, 但 I'm in my late sixties. I have been running my own lab 对于 almost 40 years. So gradually, as an assistant professor, I realized, hey, I 可以 do 这. I 可以 do science. I 可以 write papers 那 my colleagues seem to be interested in. 和 then gradually, over then the next 10, 20, 30 years, I gained 更多 和 更多 confidence. So 对于 me, it was 这 非常 gradual build up of many 不同的 experiences where I developed some confidence 那 not all of my ideas are great, of course they're not, 但 it's okay to voice my opinion. It's okay to state my ideas 和 why I believe 这 和 why I don't believe 那. So 那 was my experience.

安德鲁·休伯曼： Thank 你 对于 sharing 那, 因为 I think 人们 struggle 与 那 非常 issue. 和 clearly, showing up again 和 again over a long period of time is helpful. 但 as 你 said, learning to trust 一's ideas, just a brief anecdote when I was coming up in neuroscience, a few years behind 你, 20 years behind me, not too many decades. 但 I recall the incredible number of high profile papers on neuroplasticity 和 long term potentiation, long term depression. 这些 are terms related to the modification of synapses 那 Rob Malenka 和 Roger Nicoll pioneered. A big segment of 那 work. 和 I remember seeing 你的 names on papers, 和 I thought Roger worked 对于 你. Sorry, Roger. [LAUGHS]

Robert Malenka: I love to hear 那. [LAUGHS]

安德鲁·休伯曼： I was under the impression he worked 对于 你. 和 only later did I learn 那 你 were his postdoc.

Robert Malenka: 和 then 我们 collaborated as equals.

安德鲁·休伯曼： 你 became peers 非常 quickly.

Robert Malenka: 非常 quickly.

安德鲁·休伯曼： Roger's wonderful.

Robert Malenka: I did have the confidence, even as a postdoc, actually, even as a grad student, even though I was a little insecure 关于 my ideas. I wanted to be treated as an equal. 那's the 一 thing I did have. I 从不 felt 那 I was working 对于 somebody else. I 总是 felt 那 I was working 对于 myself 和 那 我们 were colleagues, even though my mentors had 更多 experience 和 I could learn 从 them.

安德鲁·休伯曼： I like 那 你're working 对于 yourself even though 你 have mentors. I think there's some real gems in what 你 just described. So thank 你 对于 taking the time to do 那.

Robert Malenka: Sure.

安德鲁·休伯曼： I'd like to discuss 一 aspect of reward circuitry 那 I don't think most 人们 think 关于. It's fairly straightforward nowadays. I like to think 更多 人们 know what 多巴胺 is 和 understand it, thanks to 你的 work 和 Anna's work 和 some discussions 那 have taken place on 我们的 podcast 和 other podcasts. 但 all too 经常 我们 think 多巴胺, reward, wanting, liking drugs. Okay, all of 那 is great, 但 what 关于 the truly adaptive stuff, right? 因为 it's easy to fall 进入 a discussion 大约 多巴胺 of the things 那 are bad 对于 us. 但 what I'm thinking 关于 here is social interaction. Clearly, 我们 are a social species, 和 a lot of 你的 work in the last decade 和 a half 或 so has focused on the relationship between the reward circuitry, which 你 beautifully described 对于 us, 和 social interaction 和 connection. 和 where I'm going 与 这 is ultimately, 这 has huge implications 对于 autism 和 autism spectrum disorders. I don't know if, nowadays, is it okay? 你're not supposed to call autism a disease, is 那 right? 你 hear 关于 neurotypical 和 neuro atypical, 但 I have friends who have children who are severely autistic. 和 I don't know many parents who 会 elect to have a severely autistic kid. 和 so 那些 人们 经常 会 talk 关于 it as autism 或 a child having autism. So 首先 of all, 之前 我们 get 进入 the social piece, maybe 因为 I just tabled it, how are 我们 supposed to talk 关于 autism nowadays?

Robert Malenka: I am 非常 interested in the pathophysiology of what the medical profession terms autism spectrum disorder. As 你 pointed out, 个体 living 与 an autism spectrum disorder are quite heterogeneous, 和 it 可以 range 从 个体 与 severe intellectual impairment 和 quite severe impairments in social interactions, impairments in sensory processing, impairments in lots of 不同的 aspects of 我们的 behaviors 那 are 重要. 和 I think nobody 会 say, 会 argue, 那些 个体 on the severe spectrum do not have some sort of "disorder." The issue 我们 have to be sensitive to is it's a heterogeneous disorder.

Like many 大脑 issues 那 psychiatrists deal 与, like depression, like obsessive compulsive disorder, like various anxiety disorders, it's 总是 on a continuum 和 a spectrum. So 对于 autism spectrum disorder, there are 个体 who are high functioning who, 一 could argue, have a 不同的 style of interacting socially, may have a 不同的 way of processing sensory information, 但 who 会 prefer not to be viewed as having an illness, 但 rather 会 be viewed as having a 不同的 style of living 和 interaction. 和 I think 我们 need to respect 那.

So the challenge is, again, not oversimplifying a complex heterogeneous disorder 和 both being respectful of the 人们 who don't want to be defined as having a neuropsychiatric 或 大脑 disorder, while equally being respectful of 人们 like 你的 friends 与 severely impaired children who deserve help, who deserve 研究. 和 it's a tough 一, 因为 my understanding 从, to be honest, just reading articles in the lay press 和 going to websites 从 organizations 那 philanthropically support 研究 related to autism, within 那 community of 个体 who are not researchers, 但 who have family members 或 are themselves dealing 与 some degree of autism spectrum disorder, there's disagreements 关于 what terminology to use, how to deal 与 them, 和 it's complicated.

I think 我们 just have to respect everybody. 和 if 你're interacting 与 个体, I think it's appropriate. What do 你 prefer? I do know as a medical professional, 和 尤其是 when 你're dealing 与 children, there are children who need help 和 我们're not doing them a service by saying they don't have an issue 那 我们 应该 be helping them 与 和 working on. So I hope 那 answers 你的 question beautifully.

安德鲁·休伯曼： I think it beautifully answers it 和 encompasses all sides so 那 我们 可以 move forward. So as 我们 use the term autism 或 children 或 人们 与 autism, 那's what 我们're referring to.

Robert Malenka: I think 人们 are 非常 sensitive, 尤其是 那些 个体 who are neuro atypical, who previously 可能 be diagnosed as autism spectrum disorder, 但 会 prefer to not be labeled as having a 大脑 illness. 那's fine. Once 你 are an adult, 你 可以 make 那 decision 对于 yourself.

安德鲁·休伯曼： 我们 certainly have colleagues at Stanford 和 elsewhere who, at least by my non clinical assessment, seem to fall somewhere on 那 spectrum.

Robert Malenka: 和 again, it's a continuum. Just as the experience of depression is a continuum.

安德鲁·休伯曼： As 与 depression, 你 wouldn't love a child 或 an adult any 更少 因为 they have depression, nor 会 你 love a child 或 an adult any 更少 因为 of expression of some autism.

Robert Malenka: I know the point, 我们 are being trained in the medical profession to be 非常, 和 我们的 society is going 这 way too, 非常 careful 与 the terms 我们 use 和 the labeling of 个体. So I've been taught 你 可以 say 个体 living 与 an autism spectrum disorder. Some 人们 don't like using the term, oh, 那 individual is autistic, 因为 那 可以 have some, I don't want to say derogatory meaning, 但 some labeling kind of. 但 sometimes 这 gets out of control, too, as 我们 both know.

安德鲁·休伯曼： Well, 对于 sake of fluid conversation, 我们 会 do 我们的 best, 但 我们 会 acknowledge 从 the outset 那 我们 are well meaning 但 far 从 perfect in how 我们'll handle 这.

Robert Malenka: Well put. Well put.

安德鲁·休伯曼： So, in thinking 关于 social interactions 和 leaving aside anything related to autism, 对于 the moment, it appears 那 the 回路 in the 大脑 那 mediate the desire to spend time 与 others of the same species, maybe even 与 other species like a dog, are fairly hardwired 但 modifiable. 我们 were born 与 the capacity to build them up 和 那 social behavior is highly rewarded. Is it rewarded 通过 the 多巴胺 系统? 和 what, if any, involvement is there of the serotonergic 系统? 和 我们 haven't talked 关于 serotonin yet, 但 I'd love to bring up serotonin at 这 point. Maybe 你 could educate us a little bit 关于 serotonin, 因为, gosh, if 多巴胺 is fascinating, serotonin is at least as incredible.

Robert Malenka: Yeah, great question. So I think 对于 me, the easiest way 对于 me to answer it is, actually just tell 你, my 研究 history 和 how a lab like mine at Stanford 那 at 一 point was studying what 你 和 I 会 call fairly hardcore molecular mechanisms of neuroplasticity. How do connections between nerve cells change 和 what molecules are changing? 和 pretty hardcore molecular stuff. How did I end up studying social behaviors in mice? 和 what I hope 我们'll end up talking 关于, even developing behavioral models of what I 会 define as empathy in mice. The answer is 非常 simple. My lab was working on roles of classic 多巴胺 reward circuitry 和 how it changes in models of addiction.

我们 haven't talked 关于 depression models of depression, 因为 just intuitively, hopefully, 你的 listeners 可以 understand if 一 component of depression is what 我们 call anhedonia, the inability to experience reward. Eating a donut is no longer satisfying. Having sex is no longer 那 much fun, which is a component of depression. If there's a mechanism in the 大脑 那 tells 你 something is rewarding, by definition, 那's not functioning normally in severe depression. So 我们 were doing models of depression to figure out how the 多巴胺 reward circuitry was changing, as were many other labs. 我们 were studying addiction. 那些 were the obvious ones.

和, I mean, it 可能 be entertaining to 你的 audience to learn how academic scientists think. I was thinking, 那些 are fascinating topics. They're pretty competitive. Lots of other labs were working on it. 和 I started thinking what other experiences 可能 be modifying the reward circuitry. I actually made some attempts to look at feeding behavior, 但 我们 actually 从不 pursued 那 对于 a variety of reasons. 和 那's obviously 重要 因为 there is an obesity epidemic in 这 country. 和 我们 可以 talk 关于 how the reward circuitry 和 some of the things 我们've learned 从 我们的 研究 of addiction may be helpful to understanding obesity.

但 back to social interaction. I started thinking, well, 对于 most of us, what I call a pro social, non sexual experience is highly reinforcing. Andrew, 你'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 与 friends. Actually, 对于 me, the most meaningful component of my life, other than spending time 与 my children, is spending time 与 my close friends. 和 I started thinking, well, why is 那? Why do I have such a good time going to a ball game 与 my best friend 或 going out to dinner 与 another couple 和 interacting? It's 因为, well, it's highly reinforcing. 和 if it's highly reinforcing, it must involve the reward circuitry.

和 then I started thinking, evolutionarily, it makes a lot of sense, 因为 if 你 are part of a social species, there's a lot of advantages 对于 你的 survival to be hanging out 与 other members of 你的 species in a non aggressive way. It 可以 增加 你的 likelihood to find a mate 和 reproduce. It 可以 protect 你 从 predators. I mean, 那's why any of 你的 listeners who ever watch wildlife shows 或 National Geographic shows, there's a reason all 这些 animals hang out together. It's 对于 protection 从 predators. So there are all 这些 reasons.

So, 关于, whenever it was, 13 或 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, pro social, nonaggressive interactions. Another word 我们 use is just sociability. 和 对于 a variety of reasons back then, 这 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, 和 she had an interest in oxytocin. 和 as 你的 listeners know, oxytocin is 这 evolutionarily conserved neuropeptide 那's 非常 重要 对于 parturition, having a baby born 对于 milk being produced. 和 it's gotten a lot of 注意力 as a potential love neuropeptide, as something 那 is 释放了 in 我们的 brains 期间 a positive social interaction.

There's a well known researcher in social behavior 和 bonding 研究 called Larry Young, 和 he did some 非常 重要, now somewhat classic work studying a species called the vole, in particular, the prairie vole. 和 prairie voles are a species where they mate 对于 life. It's called pair bonding. So 一 vole 会 find another vole. They basically get married, they have kids, 和 they hang out together 对于 the rest of their life. No divorce, no 50% divorce rate. 和 what Larry elegantly showed in early 天, in collaboration 与 a guy named Tom Insel, who is a famous academic psychiatrist, they showed 那 oxytocin action within the nucleus accumbens, within 这 reward circuitry, was required 和 确实 重要 对于 这 monogamous pair bonding. Having said 那, there was just a paper 那 called 那 进入 question.

安德鲁·休伯曼： 但 there's 30 years of 研究 prior to 那. I'm glad 你 brought 那 up, 因为 我们'll keep 这 contemporary. 和 the reality is 那 那 recent paper got a lot of 注意力.

Robert Malenka: 你 know the paper I'm talking 关于.

安德鲁·休伯曼： Yeah. 那 maybe oxytocin isn't playing as prominent role in pair bonding as 人们 had thought. 和 yet, folks, 那 could be true. 我们 have to be scientific 关于 这 和 be open minded. 但 there's 三 decades of work 那 speaks to the contrary. So I think 我们 want to weigh the 证据.

Robert Malenka: Yeah, exactly. 和 again, the investigators who presented the work saying oxytocin may not be as 重要. There are limitations to the manipulations they did, which they 会 agree 与. So I'm just telling 你. So, Gul Dolen was a postdoc in my lab, 和 我们 formulated a project to look at the actions of oxytocin in the nucleus accumbens in mice. 和 the reason 我们 研究 mice is they're what are known as genetically tractable organisms. 我们 have all sorts of 确实 cool 和 sophisticated tricks 我们 可以 do to probe 大脑 circuitry. The actions of neuromodulators like 多巴胺 和 serotonin 和 oxytocin in ways 那 我们 可以't do in other species. 和 I'm going to get back to 多巴胺 in a 秒.

和 what 我们 found was 那 oxytocin action in the nucleus accumbens was indeed 重要 对于 promoting sociability, probably 对于 promoting the reinforcing component of a social interaction. 和 那 surprised us. It was like, wow, oxytocin seems to be causing, 增强 the 释放 of serotonin in the nucleus accumbens, 和 那 perhaps 我们'll get to 这. 那 led me off on a whole series of experiments trying to figure out how serotonin works. Studying 这 drug 我们 may talk 关于 called MDMA, which is Ecstasy, 或 Molly, which actually causes 释放 of serotonin. So 我们 did 那 work, 和 那 got us working in serotonin simultaneously. There were some other papers reporting 那 多巴胺 释放 in the accumbens. 那 多巴胺 is 释放了 in the accumbens 期间 a social interaction, a positive, non aggressive social interaction. Truth be told, it may also be 释放了 期间 an aggressive interaction.

安德鲁·休伯曼： Some 人们 like to fight.

Robert Malenka: Some 人们 like to fight. 和 the difference here is the 多巴胺 释放 和 its role in social interactions. It's not 具体的 only 对于 a social interaction, as 我们 have talked 关于, 但 nevertheless, 那 led my lab 和 other labs to do a series of papers. I'm talking 关于 the field now showing 那, 和 I'm giving 你 a lot of information here. So how 可能 多巴胺 释放 happen 期间 a nonaggressive social interaction? It turns out 那 oxytocin is not only 释放了 in the nucleus accumbens, it's 释放了 in the home of the 多巴胺 neurons in the VTA. So, my lab 和 another lab 从 Northwestern showed 那 oxytocin 可以 actually modulate 多巴胺 neuron activity in the ventral tegmental area. So I hope I'm making sense here. I don't want to get too technical.

安德鲁·休伯曼： No, I think--

Robert Malenka: --但 it just shows how 我们 discuss 这些 neuromodulators like 多巴胺. I just brought in oxytocin. 我们're going to talk 关于 serotonin in a 秒. Unfortunately 对于 你的 listeners, they don't work in isolation. They influence each other in ways 那 I think it's 重要 对于 us to understand 和 elucidate.

安德鲁·休伯曼： 那 is not too much technical detail, 和 I think it's wonderfully rich 与 areas 对于 us to discuss. 和 I'm so 非常 glad 那 你 brought up 那 neither 多巴胺 或 serotonin 或 oxytocin work in isolation, 因为 all too 经常, 和 admittedly, sometimes even on my podcast, I'll talk 关于 这些 things in isolation as a way to try 和 simplify them a bit. 但 there's just no way 那 the 大脑 works 那 way. 对于 instance, turning on 多巴胺 和 turning off serotonin, it's a weighting of inputs, 和 I think 那 serotonin, perhaps I 应该 frame it 这 way.

Just as 经常 as 多巴胺 is framed, as 这 reward molecule 和 pleasure 和 多巴胺 hits, all too 经常, I think, in the popular press, serotonin is discussed, 和 oxytocin 二, 对于 那 matter, as 这 kind of warm, feel good, everything's mellow, not 确实 associated 与 a reward 和 reinforcement. 和 of course, it's not 那 simple. So when it comes to social interactions, it sounds like oxytocin 和 serotonin are playing a prominent role also in the accumbens. 和 那 多巴胺 is activated, too. Do I have 那 right? Okay, so I don't want to take us too far down the rabbit hole of neural 回路 function, 但 那, to me, makes at least a brief discussion 关于 the nucleus accumbens itself interesting. Like, okay, so I'm thinking nucleus, I know 那 means a pile of neurons, an aggregation of neurons. It's talking to 这 ventral striatum. So 我们 got a bunch of--

Robert Malenka: --Part of the ventral striatum, part of the subdivision.

安德鲁·休伯曼： Excuse me, I misspoke. Yeah, it's part of the ventral striatum. 和 the neurons there 可以 be active 和 communicate 与 other 大脑 areas, 但 我们're talking 关于 a lot of nuance of function.

Robert Malenka: Oh, man, I'm smiling. I don't know if 你的 audience 可以 see me smiling, 因为 I sometimes go to bed feeling it's so complicated. Oh, my God, it is.

安德鲁·休伯曼： 和 yet, could 我们 say 那 within the nucleus accumbens, there are neurons 那 are acting as accelerators 和 brakes? Is there a simple analogy 那 perhaps, while not exhaustive, 可以 still be true? 因为 那's 总是 the goal on 这 podcast. Sure, there's no way 我们 可以 be exhaustive, 但 我们 want to be as accurate as 可能.

Robert Malenka: So, a 非常 influential hypothesis, which has guided my thinking. 和 again, the trick, 你 have done a wonderful job of communicating complex scientific topics to 你的 podcast audience, 和 I congratulate 你 on 那, 和 it's a 确实 重要 role. 但 as 你 know, it's 总是 更多 complicated than 我们 want it to be as scientists, 尤其是 when 你're dealing 与 大脑 activity issues 和 how the 大脑 mediates all its amazing functions. So, historically, 我们 have thought 关于 the nucleus accumbens 和 other components of 这 ventral striatal 大脑 area as primarily being composed of 二 不同的 cell types, 和 as 你 pointed out, 一 being sort of an accelerator, something 那 promotes certain behaviors, 和 the other cell type somewhat being a break saying, don't do 那 behavior, don't perform 那 motor action. 和 it is true 那 there are 这些 不同的 cell types. It is true 那 they are modulated by 这些 modulators like 多巴胺 和 serotonin in 不同的 ways. 和 那 simplistic hypothesis, 或 heuristic 我们 call it, has been 非常 useful in making models 关于 how the accumbens does all its wonderful things.

What I'm leading up to is, unfortunately, it's a little 更多 complicated. 但 yes, there are 二 不同的 cell types. 和 at least 对于 你的 audience, 我们 可以 think 关于 多巴胺 driving the activity of 一, promoting certain behaviors 和 inhibiting the activity of the other cell type, 和 being a sort of break on certain behaviors. As long as 你 和 I, as scientists appreciate, it's not quite 那 simple. It's a little 更多 complicated.

安德鲁·休伯曼： So using 那 as a framework to think 关于 social behavior, as 你 said, pro social, non aggressive, non sexual interactions involve the choice of a lot of behaviors, 但 also the suppression of a lot of behaviors. Maybe 你're starting to sense what I'm doing here. I think 对于 人们 to understand how a single structure like the accumbens could mediate social interaction 和 reward it, what it sounds like it's doing is rewarding a certain category 和 catalog of behavioral options 和 punishing, 或 at least 减少 the probability of the occurrence of other behavioral actions. 因为 when I go to dinner 与 friends, if I know them 确实 well, I 可能 hug them. I 可能 even say something mildly inappropriate if I know the context to be safe, right? 但 at a dinner interview 或 a discussion 与 somebody I barely know, I 可能 watch my words a little bit 更多, 对于 instance.

Robert Malenka: 和 I think the accumbens 和 its associated 回路, I love the way 你 just put 那... Probabilities. It's my probability of having 这 behavior in a certain context is 增加了. The probabilities of not doing certain behaviors. 和 I think there's little doubt 那 这 大脑 area called the nucleus accumbens 和 all of its associated circuitry play a 非常 重要 role in what behaviors 你 choose to do, pursue, play a 非常 重要 role in 这些, making the decision 和 performing 这些 pro social, non aggressive, non sexual interactions. I actually also think it plays a role in empathy. I'm leading 你 there. I want to have a discussion 关于 那--

安德鲁·休伯曼： --Please--

Robert Malenka: --Again, as a mechanistically driven neuroscientist, what is frustrating 对于 me is I know a lot of the connections it's making 和 the other 大脑 areas it's communicating 与. 但 I 可以't give 你 a coherent hypothesis 或 diagram of how it all happens. [LAUGHS]

安德鲁·休伯曼： 你're still going. [LAUGHS]

Robert Malenka: What I 可以 say is, even at 我们的 current 水平 of understanding, it is leading to novel hypotheses 那 are allowing the development, perhaps if 我们 bring it back to autism, 那 are allowing the development of novel at the moment, pharmacologic therapeutics 那 可能 be helpful 对于 人们 who are not having normal pro social interactions 和 会 like to have them, 会 like to be able to function in 那 domain in a 更多 adaptive 和 productive 和 meaningful way. 和 那's the importance, in my view, of the kind of mechanistic work my lab 和 many other labs 大约 the country are doing. Even if 我们 don't have a detailed understanding of how it's all happening, 我们 可以 identify drugs 和 druggable targets, 或 even behavioral interventions 那 可能 actually help 人们, 对于 example, suffering 从 autism spectrum disorder of the sort 那 they actually want 和 need interaction, need therapeutic help.

安德鲁·休伯曼： I think looking at the social connection circuitry 通过 the lens of autism is going to be 非常 interesting 对于 us to do. I do have a question 关于 what is being selected 对于 in rewarding social interactions, 因为 obviously 我们 are living in a time where 我们 don't have to aggregate in groups, necessarily to protect ourselves physically. It helps in certain ways in certain circumstances, 但 certainly to support ourselves 和 each other emotionally. Having 人们 那 我们 可以 call on when 我们're not feeling so well, 那 我们 可以 look to 对于 resources 和 那 they 可以 look to us. 但 when 我们 go out to dinner 与 friends, 或 我们 go to a ball game 与 friends, 或 我们 interact 与 friends, I'm 非常 familiar 与 the feeling of like, well, 那 felt 确实 good. It just felt good. It gives me 能量. It actually gives me 能量 to go back 和 do other things, like spend four 天 alone 与 a bunch of papers 和 lectures, preparing 对于 a podcast, which I also 确实 enjoy. 但 when I do 那, when I go out to dinner 与 friends 或 see friends, I'm not thinking 关于 buffering myself against loneliness. When I do it, I just like the interaction.

So what sorts of evolutionary hypotheses 可以 我们 come up 与 as to why the human 大脑 is so tuned 对于 这些 social interactions? Why it's rewarded by not just 一, 多巴胺, 但 also serotonin 和 oxytocin? 三 prominent neuromodulatory chemicals in the 大脑 are devoted at 一 site in the 大脑 和 others 那 it's connected to, of course, 但 to making sure 那 我们 do 这 as 经常 as 可能 没有 giving up the rest of 我们的 lives.

Robert Malenka: Well, again, I think the answer I'm going to be able to give, I hope, it's not right, 和 it may be a little bit obvious, is in some ways it's analogous to why drugs of abuse 和 addiction are also a problem, is 那 the circuitry 那 is telling us a pro social positive interaction is so highly reinforcing, evolved over millions of years, 或 hundreds of thousands of years, whatever 那 is. 和 the only hypothesis I 可以 come up 与, 和 Andrew, 你 may be able to come up 与 better ones, is what I alluded to earlier, is 那 it was 非常 adaptive when 我们 were 更多 primitive organisms, 从不 心智 non human primates, 但 when 我们 were whatever 我们 were, to be a social species 对于 basically primarily 二 reasons, 对于 reproductive purposes, it 增加了 你的 likelihood of reproducing if 你 were hanging out 与 other members of 你的 species in a non aggressive way 和 对于 protection against predators. 和 there may be other reasons, probably.

安德鲁·休伯曼： Child rearing in 你的 absence, 你 want trusted friends 那 可以 watch 你的 offspring.

Robert Malenka: Thank 你. 非常 good point. So the 回路, the modulators 我们 use, 那 evolved over millennia, 和 as 你 pointed out, eventually, depending on the society in which 你 live, 你 didn't need 那些 social interactions 对于 protection against predators. 尽管 if 我们 look at 我们的 world now, 一 可以 make arguments both ways. If 你're in a war zone, is it better to be off by yourself? Is it better to be 与 a group of 人们? 但 so the mechanisms evolved 对于 一 purpose, 和 they don't just disappear 因为 there's no disadvantage to having 这 mechanism 那 tells us a social interaction is reinforcing.

和 I 会 still argue there's benefit 对于 reproductive purposes. 你 可以't have kids if 你're by yourself all the time. Well, 这 is actually, I think it's impossible, at least currently, 和 你 可以't find a partner 与 whom to have kids if 你're socially isolated 或 it makes it much harder. So I hope I'm answering 你的 question. 和 then, as 你 pointed out, 对于 many of us, there's a lot of positive aspects to having friendships 和 hanging out 与 你的 friends. Emotional support, emotional buffering--

安德鲁·休伯曼： --和 feeling connected. There's something 关于 feeling connected, 这 notion of feeling connected, 和 later 我们'll talk 关于 psychedelics. 但 这 notion of feeling connected has a lot to do 与 buffering loneliness. When 我们 are alone, the memories 和 the 能量, 对于 lack of a better word, 那 我们 feel in recalling social experiences 和 anticipating social experiences is 确实 powerful. 你 mentioned 那 人们 可以't have children if they spend all their time alone. I realize 你're not on social media 和 更多 power to 你.

但 there's actually a prominent discussion on social media. There's an entire culture of young 人们, in particular young men 这些 天, who, at least 从 what I understand in the 研究 literature 关于 这, are socially isolated, spending all their time online, maybe not even on social media, 但 are spending a lot of time online. Video games, hiding in electronic landscapes, digital landscapes, 和 concern 关于 心理健康 issues there, etc., concern 关于 porn, overuse 和 addiction there, etc.. 但 social media itself is an incredible phenomenon to consider in light of everything 我们're talking 关于.

Even though I am on all social media platforms 和 I am quite active there, I 可以't say 那 I've ever been on social media 和 experienced the kind of delight 和 thrill 和 persistent 能量 增加 那 I experience 与 in-person interaction. 和 yet social media, I have to assume, is capitalizing on some of 这些 same reward mechanisms in presumably the nucleus accumbens. So are there any 数据? I realize 这 is a hard experiment to do in mice, maybe impossible, 但 are there any 数据 那 你're aware of 那 shows 那 social media has a high addictive liability? 或 do 我们 even need an experiment?

Robert Malenka: I'm not sure 我们 need an experiment. I think it clearly does. I agree 与 the point 你're making. 尽管 你的 podcast audience probably doesn't know who I am. I am in my late sixties. I grew up--

安德鲁·休伯曼： --Well, they know who 你 are now--

Robert Malenka: --I grew up 之前 computers, 之前 cell phones. So I still am a believer, perhaps in an old fashioned way, 那 physical interpersonal reactions are 确实 重要. Obviously there are advantages to being able to interact over social media 对于 all sorts of reasons. There's a lot of positive 和 good 从 那.

但 back to 你的 question. 可以 我们 get addicted? I 可以't speak to social media. I 可以 speak, 和 Anna Lemki, I think, is much 更多 able to eloquently describe the issues 大约 这. I 可以 just talk 从 my own experience 那 my cell phone is 和 check, 你 know, 这 isn't social media, 但 checking my email messages, checking my texting, my text messages 对于 me has a compulsive, addictive quality, like a lever press. It's like a lever press 对于 a mouse.

和 part of 那 is my own personality. Part of 那 is the immediate feedback. So 你 get 从 a social media post, 从 seeing 你的 name mentioned, getting a message 从 一 of 你的 friends. Sure, I like getting messages 从 my friends. It means they're thinking 关于 me. It means I'm part of their world. I have no doubt it's activating my reward circuitry, not nearly to the degree 那 a hit of cocaine 或 an opioid 会 do. I don't know what else to say 关于 it. I think as a society, 我们 have to be aware of 这些 issues, 和 it's 确实 complicated how 我们 manage, 尤其是 once 你're an adult, 你 make 你的 own decisions, 对于 better 或 worse. 但 it's a huge issue, obviously, 对于 anybody who has children 或 is planning to have children 和 adults.

安德鲁·休伯曼： On social media, I see lots of accounts of 人们 那 are 18 和 older who spend a lot of time on there. 和 I'm not necessarily saying 那's a bad thing. A lot of 人们 have entire careers 那 exist on social media. It just seems to me 那 Instagram, Facebook, LinkedIn, Twitter have capitalized on 这 hardwired circuitry. I mean, to make it 确实 reductionist, the 释放 of serotonin, 多巴胺, 和 oxytocin by virtue of someone saying something to us, maybe not even a positive thing, maybe it's a negative thing. As 你 said, they're thinking of us. There's something 关于 being recognized by others. 和 maybe 这 is a good segue. 我们're heading towards empathy here. A discussion 关于 empathy.

Robert Malenka: I think 那's 非常 well put. It is capitalizing on 这些 更多 primitive neurobiological mechanisms 那 evolved 对于 purposes of reproduction 和 survival. I think 那 certainly has to be the case. 和 I think it's 重要. I mean, thank 你 对于 bringing 那 up 对于 us as a society, to be at least aware of 这. 和 it's like many things, it's not all good, it's not all bad. There are positive uses of social media, I 可以 see, 但 mostly 我们 read 关于 the dangers of it. 我们 read 关于 这些 kids who are socially isolated, who make bad decisions based on what they're seeing 与 social media. 但 anyhow, back to the neuroscience. 你're absolutely correct. It's capitalizing on 这些 mechanisms 那 evolved 对于 physical interpersonal interactions 因为 我们的 evolution didn't anticipate it, right?

安德鲁·休伯曼： Just as pornography is capitalizing on the sexual arousal reward 回路. Associated reward--

Robert Malenka: --No question 关于 it. Just as the gambling industry does. I mean, as 你 know, the Vegas casinos have full time 人们 developing algorithms 对于 how frequently 应该 a slot machine pay off. 你 know, what's the perfect amount of payoff to keep certain 个体 coming back?

安德鲁·休伯曼： So pernicious. 你 可以 tell I've been spending a lot of time 大约 addicts 和 former addicts. I've been researching some things 对于 the podcast 和 a gambling addict told me something interesting. They said the real stinger 与 being a gambling addict is 那 the next time 确实 could change everything, whereas no alcoholic says 那, 那 the next drink could change everything 对于 the better. 或 the cocaine addict doesn't think, oh, the next line of cocaine could make all of life better now 和 forever, whereas the gambling addict actually holds in 心智 the infinitesimally small 和 yet real potential 那 the next time 确实 could wipe out their debt 和 perhaps wipe out... 和 yet 我们 know they 会 lose 那, too, right? Whatever winnings they have.

Robert Malenka: 和 casinos are fully aware of 这. I have been told by friends who know they employ full time quantitative, 对于 lack of a better term, I was going to say computer geeks. I don't mean 那 to be derogative.

安德鲁·休伯曼： 和 probably neuroscientists too.

Robert Malenka: I 会 be amazed if they don't have neuroscientists who have expertise in what's called neuroeconomics 或 behavioral economics. I'm 95% sure 那 has to be the case.

安德鲁·休伯曼： I occasionally sit down to the roulette table 因为 it’s just so passive 和 easy. 和 not long ago, actually, I had the experience of winning, not a large sum, 但 a meaningful sum of money.

Robert Malenka: It's fun.

安德鲁·休伯曼： 和 I'll tell 你, my sole mission at 那 point was to get up 和 go back to my room 和 not stop at another table. 和 I confess I pulled 一 brief stop at another table, played 一 hand 和 then lost it, 和 then just got back to my room as quickly as 可能 和 then left Las Vegas as quickly as 可能.

Robert Malenka: Yeah, gambling is--

安德鲁·休伯曼： --但 they'll probably get me the next time--

Robert Malenka: --Yeah, gambling is, again, it all gets back to 这 reward circuitry, 和 the intermittent rewards are 非常 powerful.

安德鲁·休伯曼： Well, 和 你 mentioned earlier 那 the reward 系统 is powerfully tuned to remember what were the behaviors 那 led up to the rewarding experience. Nobody ever won at the roulette 或 craps table 或 poker table by getting up 和 leaving.

Robert Malenka: Right, exactly.

安德鲁·休伯曼： So I guess my 大脑 was just thinking, well, how did I win? I won by sitting down 和 putting chips on the table, not by going back to my room.

Robert Malenka: Exactly.

安德鲁·休伯曼： 和 yet I have a fair number of degrees, 和 I like to think my prefrontal cortex is working. 和 yet it was still challenging in 那 moment.

Robert Malenka: Gambling is 确实 another human activity 那's quite complicated. It 可以 be enjoyable 或 it 可以 be incredibly damaging.

安德鲁·休伯曼： 和 now 人们 are going to think I was 那 gambling addict 那 I was referred to, 但 I swear I'm not. Fortunately, I feel 非常 blessed 那 那's not my addiction. I'd like to talk 关于 empathy 和 use 那 as a framework 对于 eventually returning to 我们的 discussion of autism. 但 你 have 这 perhaps longstanding interest, 但 recent 研究 interest in empathy. Tell me 关于 这 work. I'm not familiar 与 it.

Robert Malenka: Okay. So I hope it's okay to drag in some work I've done on 这 drug called MDMA 因为 it is related. So 我们 were working on, in my lab, social behaviors, positive pro social behaviors 那 stimulated me to start thinking 关于 what are components of a positive pro social, non aggressive interaction. A common key component of 那 is having some empathy 和 compassion 对于 the 个体 你're hanging out 与. 和 it is a topic I've been interested in 对于 many, many decades. I was once a psychiatrist, 和 to get on my, whatever the word is, hobby horse, I look at the world today. I try to be optimistic again. I am a child of the '60s 和 '70s.

When I look at the world, 和 I actually just did a trip to Israel to give a series of lectures, 和 I look at the Israeli-Palestinian conflict, what 总是 enters my 心智, 和 I've felt 这 way 对于 decades, is what is 更多 重要 对于 the survival of the human species than empathy 和 compassion, than actually being able to look at another human being, even if they look 不同的 than 你, even if they have a 不同的 belief 系统 than 你, what is 更多 重要 than actually understanding 那 98% of 你的 life is 非常 相似的? 你 have some differences in how 你 look 和 the beliefs 你 have, 但 there's so much in common. So what's 更多 重要 than understanding 那 when another person is suffering, their suffering is the same as 你的 suffering 和 having compassion 对于 somebody?

So I started thinking, what is 更多 重要? 和 I'm not a politician. As 你 know, Andrew, I have no social media presence. I figured the only way I 可能 be able to contribute to efforts 那 可能 help the human species 增强 empathy 和 compassion is by studying the neurobiological underpinnings of it. 和 I didn't realize I 可能 be able to do 那 until I started studying sociability 或 prosocial behaviors in mice. 和 then I was able to have a young woman scientist, 和 I want to give her credit, Monique Smith. 你 可能 want to have Monique on 你的 podcast. She's a dynamo. She's now an assistant professor at UCSD, where 你 were. 和 Monique introduced me to a series of behavioral assays 那 I like to use the phrase, they are measurements, they are behavioral antecedents of empathy. 因为 in the world of psychologists 和 人们 who use the term empathy, it has a lot of 不同的 meanings to 不同的 人们.

I'm using it basically to mean 一 member of a species manifests some behavior 那 indicates it is being influenced by the emotional state, 或 what 我们 call the affective state, effective 与 an “a” of another member of 那 species in its immediate environment. 对于 human interactions. I just think, 我们 were talking 关于 friendships, any of us who watch a close friend suffer, it's hard. 你 want to do anything 你 可以 to help them. 那's empathy. A mother 与 their child, a good mother, hopefully, when 你 have a kid who is sick, there's nothing worse. As a parent, 你 just want to take 那 pain 和 suffering away. 那's how I'm defining empathy.

So it's my belief 那 like any complex human behavior, there are evolutionary reasons why 那 has been adaptive 和 重要 和 maintained. 和 if it's evolutionarily evolved, there are ways of studying it in 更多 primitive organisms, like mice. So I'll tell 你 some of the behavioral assays 我们're doing. 一 is, 和 I get a kick out of 这 因为 it's pretty new 对于 me, so 一 assay, 和 我们 published a paper in a journal called Science 关于 这, which is if 你 take 一 mouse, 和 in an ethical way, 你 put it in pain, 你 make its hind paw, 一 of its paws, 一 of its feet hurt a modest amount, 和 你 take another mouse 和 你 let 那, what's known as the bystander mouse, just hang out 与 the mouse 那's in pain 对于 1 小时, just 1 小时. The bystander mouse, who has experienced no physical injury whatsoever, 会 manifest behaviors indicating it is now in pain. 和 it lasts maybe four to 20 小时. 但 think 关于 那. A mouse 那 is normal hanging out 与 another mouse in pain starts feeling pain itself.

安德鲁·休伯曼： 和 the mice are able to see 一 another 和 hear 一 another?

Robert Malenka: Good point. So 你're getting to how is 那 communication happening? 和 a lot 更多 work needs to be done on it. Monique 和 her previous colleagues 和 others. 一 component of it is probably an olfactory cue, 或 what 我们 call a pheromone.

安德鲁·休伯曼： So the mouse 那's in pain is secreting an odor?.

Robert Malenka: Probably, 因为 你 可以 take bedding 从 mice in pain 和 expose the bystander mice, so 那's 一 thing. 和 I had 从不 heard of 这些 behavioral assays. 我们 developed 我们的, 和 这 is pretty cool, 和 then I'll tell 你 二 others, 和 then I'll tell 你 how it connects to reward circuitry. 我们 developed a novel assay, which is the social transfer of pain relief. Pain relief is called analgesia. 和 I thought 这 was pretty cool. 和 这 is in 这 paper 那 was published in Science a year ago.

你 take 二 mice 和 they're both in pain, modest pain. I don't want 你的 listeners to get upset. 我们 are not hurting 这些 mice too badly, 和 it is a tricky issue. Is it okay to put a mouse in pain so 你 可以, the goal is to develop better treatments 对于 human beings in pain, obviously. So 你 have 二 mice in modest pain. 你 give 一 mouse morphine. So it's now analgesic. It is no longer experiencing pain. 你 take another mouse 那's in pain, 和 你 just let it hang out 与 the mouse 那 is no longer in pain, 和 the mouse 那 is in pain 会 show behaviors indicating it is experiencing analgesia. It is no longer in as much pain.

Now think 关于 那, 和 there's actually 证据 从 human 研究 那 I 可以't speak to in any comprehensive way where it's called social buffering of pain. To be honest, I've been having some neck pain just 因为 I'm an old guy 和 I woke up on the wrong side of the bed. 和 if I'm by myself, I 专注 on 那 pain, 和 it bothers me 更多. If I'm socially engaged, I think it's not only 那 I'm not paying as much 注意力 to the pain, 但 I think there's actually some relief 从 what's known as the social buffering of pain.

安德鲁·休伯曼： Well, I'm no hippie, 但 I actually think 那 all species, including humans, are secreting molecules, mainly odorants, 那 are perhaps even acting directly as analgesics. 和 I 可以 make 那 statement 没有 worrying too much 那 人们 think I'm completely crazy 因为 我们 had Noam Sobel on the podcast 从 the Weisman who shared 与 us not 一, not 二, 但 at least a dozen ways in which humans are making molecules, 通常 odors, 和 communicating 那些 to 一 another to powerfully impact their testosterone 水平, their vasopressin 水平, their 免疫 molecules. 和 of course, Noam works on olfaction, so he's going to be biased toward 那 系统. 但 那's just 一 slice of the sensory array.

What 关于 the way 那 somebody 可以 look at us in a way 那 makes us feel good on a normal 天? Well, when 我们're in pain, just even the touch to a shoulder 可以 mean a lot. I remember going to meetings when I was an early neuroscientist, 和 I 会 probably at 那 point, have not been the type to just walk up 和 say hello to 你 因为 I wasn't in 你的 field, 和 你're 这 luminary 和 stuff, 但 I remember as I started, I'm a good guy, by the way. 你 are 非常 good.

Robert Malenka: I 总是 say hi to everyone.

安德鲁·休伯曼： I know 你 are. 和 那 statement was a reflection on me, not a reflection on 你. 但 as I advanced 通过 my career, what I found was 你'd give a talk 或 something, 和 someone in 你的 field 更多 senior to 你, who 你 respected, 会 give a nod 或 something. 那些 nods meant a lot.

Robert Malenka: Absolutely.

安德鲁·休伯曼： 那些 nods could carry 你 a long distance. I mean, obviously, 我们 want to be intrinsically driven to do the work 我们 do, 但 这 social communication 那 我们 do--

Robert Malenka: --我们're a social species--

安德鲁·休伯曼： --I think there's a whole landscape of things. So what 你're describing is incredible, 但 I think makes a ton of sense.

Robert Malenka: Yeah. So 我们 have 这 social transfer, pain of analgesia here 我们're working on, 和 there's a little bit of 证据 in the literature suggesting 这 可能 work. 和 then I'll talk 关于 reward circuitry 和 maybe MDMA 和 is it an empathogen 或 not, 和 how 那 可能 influence therapeutic efforts 对于 autism. 我们're working on behavioral models. 我们're asking the question, 会 一 mouse behave to give another mouse a reward? So it's the mouse 那's behaving 那 has to press a bar 或 nose poke 或 even experience a shock. 会 the mouse do 那 simply to give 一 of its buddies a reward?

安德鲁·休伯曼： Pure altruism.

Robert Malenka: Yeah. 我们 call it generosity, a generosity assay. 和 early 天, it looks like it 可能 be working. 和 那's a generosity assay. 我们 可以 also ask the question, 会 a mouse work? So another mouse doesn't get a shock, doesn't get hurt, which is compassion. 和 I think 这些 things are going to be working. 和 whether 你 want to call 那 empathy, I 会 call it 那. 那些 are behaviors, I like to use the term behavioral antecedents of how 我们 define empathy in human beings 和 the connection to reward circuitry. 和 the little bit of work 我们 have done on 这 is 我们 presented 证据 那 这些 behaviors 我们 call the social transfer of pain, 一 mouse experiencing pain just 因为 it's hanging out 与 another mouse.

The social transfer of analgesia. A mouse in pain getting some pain relief 从 hanging out 与 another mouse in pain, who has 那 pain relief. It seems to involve 一 component of the complex 大脑 mechanisms, seems to involve a part of the 大脑 called the anterior cingulate cortex, which human 大脑 imaging 研究 suggest is activated 期间 empathic human responses. 和 the projections of 那 area 进入 the nucleus accumbens. 那's the connection. 和 我们're interested in whether neuromodulators like 多巴胺 和 serotonin may influence 这 circuitry, 这些 connections 那 are involved in 这些 "empathic" behaviors, etc., etc. 和 我们 think drugs 可以 be used as probes of 那些 kinds of neuromodulatory mechanisms. I hope 这 is all making sense.

安德鲁·休伯曼： Makes excellent sense, 和 it's fascinating. I'm not 一 to suggest experiments to colleagues in areas where I don't work, 但 I'm going to anyway.

Robert Malenka: Yeah, please.

安德鲁·休伯曼： 一, 你're a 确实 smart guy.

Robert Malenka: I 会 value 你的 suggestions.

安德鲁·休伯曼： I love the motivational backbone to what 你're describing here 因为 I agree the world has a lot of issues, 和 what could be 更多 重要 than to 增加 the amount of empathy 和 compassion in the world? 但 一 thing 那 我们 know inhibits empathy 和 compassion is 一's own challenges 和 struggles. 和 so I'm wondering if there's a way to introduce something to 这 behavioral paradigm such 那 the working to provide another animal relief 从 pain, 一 animal working to provide relief of another animal in pain, 或 an animal working to provide pleasure reward 对于 another animal if it could be scaled 与 how inconvenient 那 work is.

Robert Malenka: Absolutely.

安德鲁·休伯曼： If I'm 非常 hungry. I mean, 我们're all taught to put 我们的 own oxygen mask on 首先 in some way too, so 那 我们 don't all die, so to speak. 但 I grew up, 对于 instance, 与 一 parent. My mother was the kind of person who 会 see, at 那 time, there were far fewer homeless 人们 on the street. Maybe they were all institutionalized, I don't know. 但 if she saw a homeless person on the street of the town 我们 lived in, she 会 literally pull over, give them money, find hotels. She had homeless 人们 living in hotels all over the town 我们 lived in.

Robert Malenka: Good 对于 her.

安德鲁·休伯曼： It was crazy. I mean, 我们 couldn't get anywhere. 那 was the problem, is 我们 会 从不 arrive anywhere on time. 和 那's my excuse 对于 总是 being late. I was positively reinforced 对于 being late. I 总是 run late, 和 I 总是 run... Incredible, right? Just a 非常 strong sense of social, fantastic connection, 那 kind of thing. 但 in any case, some 人们 are like 那. She could not experience any even modicum of inconvenience 对于 helping others.

Robert Malenka: Good.

安德鲁·休伯曼： Whereas I think most of us feel like if I'm rushing to catch a flight 和 I see someone who's struggling, I'm probably going to help them if they're in acute pain 或 it seems like a dire circumstance. 但 let's be honest, most 人们 are probably going to prioritize their own 压力 和 priorities, 对于 lack of a better word, when the situation 经常 calls 对于 us to set 那些 aside 和 tend to 人们 那 are suffering. So if there was a way to introduce a probe of the interplay of circuitries 那 involve how convenient 或 inconvenient it is.

Robert Malenka: Fantastic.

安德鲁·休伯曼： Like if 我们're well fed, it's pretty easy to go out 和 gather 和 distribute food 对于 others. 但 if 我们're hungry, 我们 tend to 专注 on 我们的 own hunger.

Robert Malenka: So 首先, in full disclosure, even though I'm studying empathy 和 compassion, I 可以 look in the mirror 和 say, I probably don't practice it nearly as much as I 应该. I'm thinking of 你的 example. If I was late 对于 a plane, I'm not sure I 会 stop 和 help somebody. 和 I'm not saying--

安德鲁·休伯曼： --I think it depends on what sort of suffering exactly. If they're hemorrhaging on the side--

Robert Malenka: --Of course--

安德鲁·休伯曼： --我们 all 会 of course, 但 a flat tire, right? 你 可能 think, oh goodness, do I have time 对于 这?

Robert Malenka: Yeah, exactly. So I'm not proud of 那 statement. 但 back to 你的 question. Yes, I think absolutely, 我们 可以 design experiments where, 之后 我们've established the basic phenomenology, then 我们 可以 take 我们的 subject animal 或 mouse 和 put it 进入 certain circumstances. If it's hungry itself, 会 it work as hard to give another animal food? I mean, it's a good question 因为 I'm not sure what the outcome 会 be. 一 could predict it 可能 work harder 因为 it understands the "hunger" 更多.

安德鲁·休伯曼： I love 那.

Robert Malenka: 或 it could be, of course it's not going to work hard 对于 another animal to get a food reward 因为 it's starving itself 和 it needs to take care of itself 首先. It's a great question. 我们're also asking questions 关于, do 你 have to know 你的 buddy mouse, right? Are 你 更多 可能 to behave in a generous 或 compassionate way if 你 grew up 与 那 mouse in the way 我们的 mice grow up in academic environments? 和 if it's a stranger, how 会 你 behave? How 会 你 behave if 你 had a fight 与 那 mouse previously? 和 it also matters, did 你 win the fight 或 did 你 lose the fight? Intuitively, as 我们 probably 会 all guess, I'm 更多 可能 to help somebody I defeated in a fight previously, 因为 in the hierarchy, I'm the dominant 一. I'm probably 更少 可能 if 那 person beat me up. So all 这些 are great questions. I think 我们 可以 研究 them. I also think there are ways 我们 可以 研究 这些 kinds of interactions in human 受试者. Not 那 I am going to do 那 myself.

安德鲁·休伯曼： Someone at Stanford 会. [LAUGHS]

Robert Malenka: Yeah. So I think there's also an opportunity, 和 I'm happy to discuss how neuromodulators, like in particular serotonin, 但 also perhaps 多巴胺 和 oxytocin, may influence the circuitry in the 大脑 mechanisms 那 are mediating what I term empathic behaviors.

安德鲁·休伯曼： Let's return to autism.

Robert Malenka: All right.

安德鲁·休伯曼： Does autism involve a lack of empathy? Does autism involve a restructuring of the reward 系统 大约 social interactions?

Robert Malenka: Maybe.

安德鲁·休伯曼： Considering the 秒 question 首先, I could imagine, 对于 instance, 那 there are variations in 大脑 wiring 那 会 make it such 那 a kid who then becomes an adult gets a tremendous amount of reward 从, I don't know, math, designing mugs, any number of activities. 但 那 通过 some variation in 大脑 wiring social interaction, spending time 与 friends is just not as socially rewarding. It just doesn't feel good in the moment, doesn't necessarily feel bad, 但 it's not selected 对于. 和 is there any 证据 那's the case in children who are classified as autistic 或 having autism? I want to be clear. I am not a world expert on pathophysiology of 个体 与 autism spectrum disorder. I have read some of the literature. I do 研究 mouse models of genetically based autism spectrum disorder.

Robert Malenka: So the answer is yes, there have been imaging 研究, 和 again, so certain members of 你的 audience don't get mad, remember 我们的 earlier conversation? 我们 made the point 那 autism spectrum disorder is a highly heterogeneous set of behavioral symptoms 与 wide variation in how 这些 symptoms manifest in each individual. So 我们 cannot make blanket statements 那 个体 与 autism spectrum disorder are 这 或 那. 但 there are 研究 both in human beings 和 mice 那 suggest 那 the reinforcing component of a social interaction is much 更少 或 lacking in 我们的 models of autism spectrum disorder 和 certain 个体.

An 重要 point is, is 那 just genetically wired? Was 那 因为 in their early experiences, they weren't able to get the sensory stimuli 那 tell them 这 is a reinforcing social experience unknown, 或 at least 那些 are topics 那 I think are worthy of investigation. Do 个体 或 mice 与 autism spectrum disorder lack 或 do not have the capacity 或 the same experience of empathy? Again, a 非常 complex topic in question, 和 it's 非常 可能 对于 some 个体, the answer is yes, meaning they do lack some of the neural mechanisms 那 allow them. 但 那 probably doesn't apply to everybody. I 可以 say in 我们的 mouse models of social interactions 和 我们的 mouse models of "empathy," 我们的 mice show deficits 和 那些 deficits 可以 be rescued, meaning 改善了 upon by manipulations of certain neuromodulatory 系统, in 这 case, the serotonin 系统, by giving drugs, including a drug called MDMA 或 Ecstasy. So I hope I'm answering 你的 question. I think 这些 are worthwhile 受试者 对于 investigation. I think there's a lot of value in studying them.

安德鲁·休伯曼： Let's go back to serotonin in the nucleus accumbens. 我们 会 get 进入 这 in a bit 更多 detail when 我们 discuss MDMA. 但 I've now spent a lot of time 与 a recent paper of yours--

Robert Malenka: --确实? Which 一?

安德鲁·休伯曼： The MDMA paper.

Robert Malenka: The Boris Heifets 一?

安德鲁·休伯曼： Yeah, 那 parsed the relative roles of 多巴胺 in the nucleus accumbens versus serotonin in the nucleus accumbens. By the way, folks, by the time 这 episode comes out, an episode all 关于 MDMA itself 和 its modes of action 会 have already aired, 和 你 可以 find 那, 但 even if 你 haven't heard 那, MDMA is an amazing molecule 因为 it profoundly 增加 多巴胺, 和 那's why the word methamphetamine is actually in MDMA. Still a surprise to many 人们 to hear 那, 但 it also robustly 增加 serotonin transmission.

和 what I love 关于 the paper 从 你的 lab 那 explored 这 is 那, at least by my read of the 数据, it showed 非常 convincingly 那 it's serotonin 释放了 in the nucleus accumbens 那's responsible 对于 the prosocial effects of MDMA, whereas oxytocin, 这 thing 我们 talked 关于 earlier 那 everyone assumes is the pair bonding molecule, the molecule of love, both in humans, now there's a 研究 in humans 和 in the mouse work 那 你've done, doesn't seem to play as prominent a role in the social enhancement 那 MDMA causes. 和 the reason I'm asking 这 in the context of autism is 那 对于 a long time, there was excitement 关于 the idea 那 oxytocin nasal sprays 可能 make autistic kids 更多 excited 关于 social interactions, 更多 tuned to social interactions. 首先 question is, is there any 证据 那 increasing oxytocin in a child 或 adult 与 autism makes them somehow 更多 social 或 desiring 更多 social connections? I'm not aware of any.

Robert Malenka: I think it is worthwhile. It has been studied. I don't think 我们 可以 close the door on the potential therapeutic uses of oxytocin 从 the 人们 I know who are much 更多 expert in 这 than I am. I think most of the clinical trials have been pretty disappointing, 与 a lot of hope 那 intranasal oxytocin 会 promote 更多 positive pro social experiences. I don't think the door is shut yet. There may be 不同的 ways of administering it. There may be ways of making a 不同的 type of oxytocin 那 可能 be beneficial. I have a colleague at Stanford who's actually looking at a related neuropeptide called vasopressin, 和 she's finding some potential benefit 从 那. 和 vasopressin 和 oxytocin are closely related to each other. They 可以 even activate some of the same, what 我们 call 受体 in the 大脑. So I don't think the door is closed on the possibility of oxytocin 或 related therapeutic agents having some therapeutic potential.

The 证据, as far as I'm aware, is not there yet in terms of MDMA, again, complicated story. As 你 pointed out, MDMA, its major molecular targets, don't want to get too technical here, are the serotonin vacuum cleaner, the molecule 那 vacuums up serotonin, 和 the 多巴胺 vacuum cleaner, the molecule 那 vacuums up, 和, excuse my language, sucks up 多巴胺 when it's 释放了, 因为 it's an amphetamine derivative, as 你 correctly pointed out, it not only prevents 这些 proteins, 我们 call them, 这些 molecules, 这些 vacuum cleaners, 从 vacuuming up the 多巴胺 和 serotonin when it's 释放了, it actually causes it, how do I, I don't want to use the terms to vomit out 多巴胺 和 serotonin--

安德鲁·休伯曼： --那's what I say on the podcast--

Robert Malenka: --Am I allowed to say 那?-- [LAUGHS]

安德鲁·休伯曼： --when I talk 关于 synaptic 释放, I'm known 对于, on my solo episodes, 对于 when I talk 关于 synaptic 释放, I'll say 那 they [MAKES VOMITING SOUND] they vomit out. [LAUGHS]

Robert Malenka: So what amphetamine derivatives--

安德鲁·休伯曼： --但 你 work on synaptic transmission. 那's almost an insult to a [inaudible] synaptic transmission.

Robert Malenka: What MDMA does is it actually calls what's known as a reverse transport. It not only prevents the vacuum cleaners 从 sucking up the 多巴胺 和 serotonin, it causes it to spew out 多巴胺 和 serotonin. So imagine if 你的 vacuum cleaner started, the pressure in 你的 vacuum cleaner reversed, 和 all the dirt 你 collected started being spewed out. Now, the 一 difference 对于 MDMA, 和 it's a fascinating topic, I hope 我们 have time to talk 关于, is why does MDMA, qualitatively, 对于 most 人们, give human 受试者 a 不同的 experience than cocaine 或 methamphetamine, 或 尤其是 methamphetamine.

安德鲁·休伯曼： Presumably, it's the fact 那 there's so much serotonin.

Robert Malenka: Exactly. 和 so if 你 actually get 进入, 和 这 is why, 对于 你的 audiences, 这 is why hardcore molecular science 可以 actually teach us something 关于 complex human behavioral phenomena, such as social interactions 和 addiction, at least the hypothesis 我们 propose 和 others in the field. It's not just, science is not done in isolation. So I want to give credit where creditors do. 我们 did not define the following, 那 MDMA affects the serotonin 系统 更多 than the 多巴胺 系统. So it's not 50/50. Maybe it's 70/30, 80/20. 和 那's 因为 the molecule itself of MDMA, again, I'm trying not to use language, it binds to, has a higher affinity, it likes to bind to 和 influence the serotonin vacuum cleaner 更多 than the 多巴胺 vacuum cleaner. It's still affecting both, 但 it's not 50/50. It's 更多, whatever, 70% serotonin, 30% 多巴胺. 和 then it does influence oxytocin in 非常 complex ways, which is a further technical discussion. There was just a nice paper 那 came out 那 reported 那 serotonin releases in a hypothalamic structure, which, again, the hypothalamus, 你 可以 explain to 你的 listeners.

安德鲁·休伯曼： A marble-ish size structure above the roof of 你的 mouth, responsible 对于 sex, 温度 control, feeding 和 satiety, 和 a bunch of other things critical.

Robert Malenka: 和 it's a home of neurons 那 produce oxytocin.

安德鲁·休伯曼： Thank 你.

Robert Malenka: So 这 paper reported 那 when serotonin is 释放了 in the hypothalamus, it activates 和 causes the 释放 of oxytocin 那's in the hypothalamus. 我们的 work in the reward circuitry suggested oxytocin. So 那's serotonin upstream of oxytocin in the hypothalamus, where 我们 were looking in the accumbens, it was the opposite. Oxytocin caused the 释放 of serotonin. So the point to 你的 listeners is the 大脑 is unfortunately complicated. It's tractable. 我们 like to come up 与 general hypotheses 和 principles, 但 sometimes the devil's in the details, 和 我们 确实 need to probe deeper.

So back to 你的 question 关于 我们的 previous paper 和 多巴胺 和 serotonin. So what 我们 proposed, which is far 从 nailed down, is 那 MDMA, 因为 it is an amphetamine derivative, does influence 多巴胺 释放 和 the 多巴胺 系统. 和 some of my colleagues in the MDMA field, who I respect enormously, don't like me to say 这, 但 I'm going to say it anyhow. Remember earlier in the podcast, 我们 talked 关于 不同的 substances having addictive liabilities? Doesn't mean a substance is automatically addictive, doesn't mean it's automatically not, it's a continuum, 和 I 会 argue 那 MDMA does have some addictive liability 因为 it is an amphetamine derivative.

安德鲁·休伯曼： It feels good.

Robert Malenka: 和 it feels good. 和 so there are 个体 那, 尤其是 as 你的 listeners may know, MDMA has gotten a lot of 注意力 因为 it's in a therapeutic trial 那 looks 非常 promising as an adjunct to psychotherapy 对于 post traumatic 压力 disorder. 和 the FDA, the part of 我们的 government 那 approves 或 disapproves the legal distribution of therapeutic drugs, may end up approving MDMA 对于 certain uses. The point being is 那 if it gets approved, my personal feeling is it 会 have some addictive liability. It also has 这 非常 powerful, what 你 和 I 可能 term Andrew, a pro social effect. Some 人们 even call it an empathogen. 那's a little controversial, meaning it 增强 你的 capacity 对于 empathy, to experience the emotional state of another individual, to want to understand 那 person's experiences 和 emotional state.

和 what 我们've suggested is 那 the addictive liability is mostly, 尽管 not solely, being, mediated by its actions on the 多巴胺 系统, whereas its positive, 更多 pro social effects 和 perhaps its empathogenic effects are 更多 可能 to be mediated by its interactions 与 the serotonin 系统 in 这 reward circuitry. 和 我们're actually doing a lot of work to test 那 hypothesis. 我们're actually testing MDMA in 这些 behavioral models of empathy in mice, 和 it looks like 我们的 hypothesis is being supported. The other thing to drive 你的 listeners crazy 关于, sorry, listeners, how complex the 大脑 is. If 你 think it--

安德鲁·休伯曼： --Listen, neither 你 nor I were consulted at the design phase, 和 so 我们 don't have to apologize 对于 the 大脑's complexity.

Robert Malenka: [LAUGHS] 因为, trust me, as a scientist, I wish I could keep things as simple as 可能. 那's what good science is. It turns out serotonin is produced by neurons in another part of the 大脑 与 这 wonderful name called the dorsal raphe nucleus. 和 it turns out the serotonin neurons talk to the 多巴胺 neurons 和 influence the 多巴胺 neurons. It's, again, the point 我们 made earlier in 你的 podcast, even though it's fun 和 useful both 对于 你的 listeners 和 as scientists to think 关于 这些 powerful chemical messengers in isolation, 因为 那's how 我们 可以 make progress scientifically.

It's how 你的 audience 可以 understand some of the concepts 那 have been elucidated 从 大脑 研究 over the decades, 但 they don't work in isolation. They influence each other. They communicate 与 each other. 我们're actually doing 研究 showing 那 serotonin 释放 in the accumbens actually modulates 多巴胺 释放. So it gets crazy complicated. 但 你 可以 still develop simplistic hypotheses, like, as I was saying, 关于 MDMA, where abuse, addictive liability, 和 some of its reinforcing qualities, which 你 just mentioned, MDMA, a lot of 人们 find it fun to take it, is probably mostly being mediated via the 多巴胺 系统, 和 some of its social effects are being mediated by the serotonin 系统. 我们're actually doing 研究 to figure out whether the reinforcing component of a social experience requires 那 多巴胺 释放. Probably does.

安德鲁·休伯曼： 那's what I'm most interested in, 确实, in the context of MDMA. 和 我们 应该 just mention, 因为 我们 do like to mention 这些 caveats. Yes. 和 I 可以 say 这 因为 I participated in a trial 与 MDMA. It is a 非常 pleasant experience. It's certainly not 对于 everybody. It still is a schedule 一 drug at 这 moment.

Robert Malenka: Absolutely.

安德鲁·休伯曼： So 你 可以 go to jail 对于 possessing 或 selling it. In fact, there was a big bust recently in Canada 和 another 一 in Brussels. Large amounts of MDMA collected. 那些 人们 are probably going to go to prison 对于 a long period of time. So 你 don't want to take it 或 possess it. It's illegal. 我们're talking 关于 clinical trials here. 但 also the fentanyl issue. There's a lot of fentanyl contamination.

Robert Malenka: 和 I was just going to mention it to 你的 listeners.

安德鲁·休伯曼： So 我们'd be remiss if 我们 didn't mention. A lot of 人们 are dying thinking 那 they're taking 一 drug when they're taking another. So 我们 are not encouraging the use of 这些. 但 I 会 say 那 the subjective experience of MDMA, provided it's done in the appropriate clinical setting, it's actually, MDMA doesn't contain other things dosed correctly, etc., is a pleasant 一, 对于 sure. 和 my sense is 那 the 多巴胺 释放 is reinforcing the experience, 那 the context 那 serotonin is providing 与 a social context 和 the word context there becomes 重要 when 我们 think 关于 back to the 90s when there were a lot of raves 和 人们 were also getting, I guess, positive feedback 从 the interactions they were having, dancing all 夜间, partying 与 friends, etc.

I think 那 returning to the issue of autism 和 the role of serotonin, so in autism, there seems to be 更少 of a reinforcement 通路 对于 certain kinds of social interactions in some 个体 与 autism. 和 I'm aware 那 there are some prescription treatments 对于 autism 那 capitalize on the serotonergic 系统 和 多巴胺 系统. So is it fentamine?

Robert Malenka: To my knowledge, the only FDA approved pharmacologic therapeutic 对于 个体 与 autism spectrum disorder is actually, oh, God, I'm just blanking, it's not a serotonergic drug, I have to look it up. I want to say risperidone 对于 agitation. There is no drug 对于, 对于 lack of a better term, the social deficits. There's no FDA approved drug. If 你 look at the literature, psychiatrists 和 个体 与 good intention have tested the utility of traditional serotonergic drugs like Prozac, SSRIs.

There are drugs known as SNRIs, drugs 那 influence serotonin 释放, 和 another neuromodulator 那 你 know well, 去甲肾上腺素 和 at least well done clinical trials, which in my view, as an academic, are 非常 重要. None of them have shown efficacy. Having said 那, there are several companies, 和 full disclosure here, I am the founder of a small biotech called Maplite Therapeutics, 和 I'm not advertising 对于 Maplite. I'm just doing a full disclosure. It was founded 与 Karl Deisseroth, who 你've had on 你的 podcast, 和 an entrepreneur in San Francisco named Karoly Nikolich. 和 我们 have a phase 二 trial. Phase 二 trial means it's a safe drug. 我们've done all the safety work, 和 it's a drug 那 targets a subtype of 受体 对于 serotonin. Serotonin works on many 不同的, I don't know, what word 可以 I use other than 受体?

安德鲁·休伯曼： No, listeners of 这 podcast 会 probably be familiar 与 受体, sort of parking spots 对于 molecules. Yes. The paper I was referencing earlier 从 你的 lab, it talked 关于 serotonin 1B 受体 being particularly 重要.

Robert Malenka: The point being is I do have an interest in 这. 可以 你 use the type of discoveries 我们've made in mice? 可能 it actually have any relevance to human beings, in particular 那些 who, some of which have some sort of sociability deficits? Other companies are pursuing 这, too. So MDMA itself, there has been. I don't know if it's ongoing. There's a well known organization. I don't know if 你've ever had anybody 从 MAPS on 这 podcast. The Multidisciplinary Association 对于 Psychedelic 研究. MAPS deserves a lot of credit 对于 being a pioneer in saying, in particular 与 MDMA, promoting the idea 那 这 drug deserves rigorous 和 ethical 研究. 那's at least my view 和 MAPS, which was founded by an individual named Rick Doblin, deserves enormous credit 对于 their 30 year effort to make it allowed 和 legal to actually 研究 MDMA.

The point I'm making is I know MAPS, 和 perhaps others, have done some small trials studying MDMA in 个体, high functioning 个体 与 some form of social anxiety. I'm saying 这 因为 这 is public. There's another company called MindMed, which is 一 of the publicly traded psychedelic companies, 和 这 is on their website. Full disclosure, I am on their scientific advisory board. They are gearing up to do a trial of a, I don't want to get too technical, of a certain form of MDMA. There are 二 不同的 types of MDMA. They have 这些 horrible names called enantiomers. So the MDMA 那 is used 对于 clinical trials 那 MAPS, MDMA is a molecule, 和 it has mirror images of itself, 和 一 has the name RMDMA 和 一 has the name SMDMA, 和 they're called the enantiomers 因为 they're mirror images of each other 和 other labs over the years, not my lab, I deserve no credit 对于 这, have done some 研究 to suggest 那 the S enantiomer is the 一 那 has a higher interaction 与 the 多巴胺 系统, 和 the R enantiomer has a higher interaction 与 the serotonin 系统.

安德鲁·休伯曼： Interesting.

Robert Malenka: If 你 look at the literature on autism spectrum disorder in human 受试者, there's a bunch of papers suggesting serotonergic 系统 are malfunctioning in 个体 与 autism spectrum disorder. 和 if 你 look at reviews I've written 或 any of my papers, 我们 probably cite some of the reviews.

安德鲁·休伯曼： It's clear 那 serotonin is playing some role in social interactions, at least in mice 和 almost certainly in humans as well. It's hard to imagine, based on 数据 从 everything 从 SSRIs to neurotoxic lesions of the human 大脑, etc., 那 it's not also playing at least a 相似的 role in humans.

Robert Malenka: Right, 和 I fully agree 与 那. 和 as 我们 were discussing, there's a modestly extensive clinical literature, meaning literature 从 human 受试者, suggesting 那 some aspects of 大脑 系统 那 utilize serotonin as 一 of their signaling molecules, 一 of their neuromodulatory mechanisms, may not be functioning in some populations of 个体 与 autism spectrum disorder. So based on 那, based on my lab's work on the role of serotonin in modifying reward circuitry, its role in pro social behaviors, 和 the biggest clue, which I think 你 会 agree 与, Andrew, is 这 drug, MDMA. I mean 这 is why, I am not a druggie myself, I am a child of the '60s 和 '70s, which means I'm 20 years older than 你, Andrew. I did experiment, like everybody of my generation, 与 psychoactive substances in the 70s, so I don't want to lie 关于 my experiences. I also 会 say, like many neuroscientists, my experiences 与 psychoactive substances stimulated my interest in neuroscience. How do 这些 substances work? Why, when I was a young kid, the 首先 time I got drunk on beer, why is 那 happening?

但 更多 seriously, I use drugs in my 研究 as powerful probes of 大脑 function 与 the advantage 那, 和 now I'm talking scientist to scientist 与 你, Andrew, they have molecular targets 那 我们 可以 manipulate in rigorous ways. 我们 可以 figure out where in the 大脑 they act using the modern tools of neuroscience, which 你的 audience may not know 关于. I'm saying 这 to 你, conditional knockout mice, rescue experiments. 我们 可以 do all 这 fancy stuff, 和 我们 可以 use drugs to 研究 even things as complicated as empathy. 和 I 确实 do believe 那 it's why I've been interested in MDMA 对于 decades, is there's a clue there. How does a drug 那 has molecular targets in the 多巴胺 neuromodulatory 系统, in the serotonin neuromodulatory 系统 have such a powerful effect, which is relatively 具体的 on social interactions? It doesn't make 你 want to go eat 更多 donuts. I don't know, 对于 me, there's a clue there. There's something 确实 重要 从 那 phenomenological observation in the human experiences 那 我们 可以 learn 从.

安德鲁·休伯曼： I completely agree 关于 MDMA, 和 我们've done a couple of podcasts 关于 psilocybin 和 by extension, LSD, 因为 even though there are differences there, psilocybin, LSD, as far as 我们 understand, largely work 通过 activation of the serotonin 2A 受体, broadening of a 大脑 network connectivity. So again, it's serotonin, serotonin, serotonin, 但 不同的 受体, 非常 不同的 subjective experience. 和 I guess perhaps the best way to describe it is 那 LSD 和 Psilocybin are almost 总是 considered mystical in their subjective effects, whereas MDMA 可以 be an empathogen, an actogen, 和 so serotonin acting 通过 不同的 受体 系统, impacting 和 creating 非常 不同的 subjective experiences. I also agree. I think MDMA is particularly interesting 对于 the neuroscientist, perhaps also 因为, at least to my knowledge, there is no substance in nature, no plant, no mushroom, no ergot, no mold 那 creates 这 增加 in 多巴胺 和 serotonin simultaneously.

MDMA is a synthesized molecule, 和 so it may be 一 of the, again, highlighting all the safety issues 和 things 我们 talked 关于 之前. It may be 一 of the great, at least experimental probes of the 大脑 那 humans have developed, 和 it may be 一 of the great therapeutic probes 那 folks like MAPS are now doing such fantastic work on. So I'm 非常 excited 关于 what's happening 与 the 研究 on MDMA, 和 I'm so glad 那 你的 laboratory has parsed some of the relative roles of serotonin, the 受体 involved. Since 我们 mentioned serotonin 2A 对于 psilocybin 和 LSD, 我们'd be remiss if 我们 didn't say 那 这 wonderful paper 那 我们 会 provide a link to in the show note captions. By the way, folks, 那 Rob Malenka here's lab focused on the serotonin 1B 受体, so even just differences in 受体 subtypes leading to profoundly 不同的 subjective outcomes, I find 那 to be just 一 of the most 重要 areas 那 一 could even think 关于, let alone work on.

Robert Malenka: Thank 你. I appreciate the compliment. I 会 also say, like everything 我们're finding, it's not all 关于 only serotonin 1B, 但 as 你 know, again, pointing to the amazing 和 powerful complexity of the human 大脑 或 the mammalian 大脑, there are 16 不同的 serotonin parking spots 或 受体 那 are distributed in 不同的 大脑 areas in complex ways. 和 so 那's daunting. 但 it also offers possibilities 对于 developing 非常 novel therapeutic agents 那 activate 或 inhibit 这些 in complex ways, hopefully 对于 therapeutic benefit.

安德鲁·休伯曼： So, 之前 我们 conclude, I'm 非常 curious to get 你的 opinion on what 你 see as the landscape of the work on psychedelics 和 MDMA, which isn't 确实 a classic psychedelic, 但 all 这些 drugs 那, as 你 pointed out 期间 你的 youth, were used recreationally 和 对于 心智 exploration 和 expansion 和 are now being probed as potential therapeutics 对于 various 心理健康 challenges, as well as potentially expanding consciousness, empathy, 和 all of 那. I mean, not getting 进入 the details of the legal issues 那 have to be overcome, not even necessarily talking 关于 the clinical trials 或 the 人们 doing the work in 不同的 laboratories, 但 just, I have to imagine 这 must amuse, tickle, surprise 你. I mean, how do 你 feel 关于 what 你're seeing now? 因为 it is a 非常 exciting time 对于 这些 compounds.

Robert Malenka: It tickles me 和 excites me 与 the appropriate caution. So I do think drugs are 非常 powerful probes of 大脑 function. I think 这 class of drug, which, as 你 correctly pointed out, 人们 use the term psychedelics scientifically. When pursuing their understanding, their therapeutic potential, their mechanism of action. It's 更多 useful to divide them up 进入 不同的 categories.

The classic hallucinogens, which are LSD 和 psilocybin, the intact 或 empathogens, which is MDMA, which is 确实 a qualitatively 不同的 drug. There are other substances which 我们 don't have time to talk 关于, like ibogaine 和 ayahuasca, which are 非常 complex, 和 peyote. 但 nevertheless, I am tickled 和 excited as a child of the '60s 和 '70s. 但 I am also not evangelical 关于 their use 和 their therapeutic potential. So as 你 可以 imagine what I'm going to say, I think they 应该 be the subject of rigorous, sophisticated, 和 most importantly, ethical 研究. I think 我们 could learn a lot 关于 how the 大脑 works 和 its amazing capabilities. I think they may notice, I say may have therapeutic potential, 但 I do not think they're going to be miracle cures.

和 I do worry, as somebody who lived 通过 the '60s 和 '70s 和 watched, 因为 of the history of Timothy Leary 和 his colleagues, 和 the political landscape of how they were being used 和 promoted, I am cautious 那 这些 substances need to be studied scientifically 和 rigorously, 和 I hope 那's the case. 和 I want to caution 你的 audience 那 not everybody 应该 take 这些 substances. They are not miracle cures. 和 while they certainly may be of benefit to certain 个体 who are suffering, 和 they certainly may provide unusual 和 "mystical" experiences 对于 certain 个体, I am 非常 concerned 那 there are 个体 out there 那 会 gain access to 这些 substances 和 have 非常 bad experiences, 因为 anybody who grew up in the '60s 和 '70s knows all 关于 bad trips, 和 truth be told, I have had a bad trip 或 二 in the '70s, 和 I'm glad I did, 因为 it made me...

I have no idea what a suicidal depression feels like where 你 are experiencing such a darkness, such a lack of hope 那 a rational decision is to end 一's life. 和 I think the closest I ever came to 那 experience is a bad trip on LSD. 和 I do have concerns 那 if 你 look at the clinical trials 那 have been done, the well done, not the anecdotal, I went 和 saw some psychedelic therapist 那 a friend recommended 和 it did wonders 对于 me. 但 the well controlled clinical trials 那 are being done by certain biotechs, some academic institutions, they have 非常 strict, what are known as inclusionary 和 exclusionary criteria 关于 who is allowed to participate in the subject, 和 they rule out a lot of 人们. So I don't mean to be overly cautious, 但 I do worry 那 if some 人们 take 这些 substances 和 bad things happen, it 会 slow down the excitement 那's currently happening, 和 it 会 make it 更多 difficult 对于 serious human 受试者 researchers, preclinical researchers, to 研究 这些 substances in the way they deserve to be studied. So I hope 那 articulates my viewpoint.

安德鲁·休伯曼： I think it does, 和 thank 你 对于 那 viewpoint. It's an 重要 counterbalance on a lot of the excitement 那 我们 hear 关于 这些 天. I think the state of Kentucky just recently decided to give $42 million 从 the opioid lawsuit settlement 与 Purdue pharmaceuticals to the 研究 of ibogaine. So there's a lot happening.

Robert Malenka: Just to be clear, I think there's no problem 与 那, 和 I actually 会 support 那. As long as the 研究 of ibogaine are done thoughtfully, carefully, 和 ethically, I see no problem 与 testing its efficacy in certain mental illnesses 和 addiction. 和 it's actually a topic I know a little bit 关于, 但 我们'll save 那 对于 another time.

安德鲁·休伯曼： Great. Well, 首先 off, I want to thank 你 对于 coming here 和 sharing 你的 knowledge 与 all of us. 对于 me, it's been a real thrill. 和 I also just want to thank 你 对于 the incredible amount of work 那 你've done over the years. I know it's still ongoing. 你're by no means retiring. I certainly hope not. 但 I'm sure the listeners have now gotten a clear picture of the enormous number of contributions 和 areas 你've worked on everywhere 从, as I mentioned earlier, neuroplasticity at the cellular 水平, molecular 水平, addiction, work relating to social cognition 和 social interactions, rather as it pertains to autism models, 和 now psychedelics 和 empathy, 和 on 和 on 和 again, trained so many prominent scientists in 我们的 field, 和 to take time out of 你的 schedule to come sit here 与 us 和 share some of 那 knowledge 和 stimulate 我们的 thinking 和, as 你 mentioned, raise still 更多 questions 那 need to be resolved is a real privilege. So thank 你 ever so much. 和 indeed, as 你 just mentioned, 我们'd love to have 你 back again 对于 another conversation.

Robert Malenka: All I 可以 say is I want to thank 你 对于 having me. I was a little hesitant 或 nervous 关于 coming here, 和 now I want to come back. So 那 was a blast, what I just did 与 你, 和 I'd be happy to continue 这 conversation anytime. So thank 你 对于 你的 非常 sophisticated 和 thoughtful questions.

安德鲁·休伯曼： To be continued.

Robert Malenka: Yeah, to be continued.

安德鲁·休伯曼： Thank 你 对于 joining me 对于 today's discussion, all 关于 neuroplasticity, reward 系统, social connection, 和 empathy 与 Dr. Robert Malenka. If 你're learning 从 和 或 enjoying 这 podcast, please subscribe to 我们的 YouTube channel. 那's a terrific, zero cost way to support us. In addition, please subscribe to the podcast on Spotify 和 Apple. 和 on both Spotify 和 Apple 你 可以 leave us up to a five star review. If 你 have questions 对于 me 或 comments 关于 the podcast 或 guests 那 你'd like me to consider hosting on the Huberman Lab 播客, please put 那些 in the comments section on YouTube. I do read all the comments.

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