How Food Choices Shape Memory, Cognition & Cravings | Dr. Scott Kanoski

饮食选择如何影响记忆、认知与进食渴望 | Scott Kanoski 博士 Scott Kanoski 博士阐述了富含精制糖、饱和脂肪以及晚期糖基化终产物的饮食如何破坏肠道微生物群，并导致持久的依赖海马体的记忆损伤。对话详细探讨了通过迷走神经进行的肠脑沟通，说明了进餐如何协调海马体乙酰胆碱峰值以编码情景进食记忆，以及现代超加工食品如何削弱内感受感知。他们还分析了内源性与药物性 GLP-1 机制的差异、非营养性甜味剂的代谢影响，以及多巴胺强化和催产素信号如何调控进食行为。 青少年时期摄入高糖或超加工垃圾食品会导致依赖海马体的记忆持续受损，这种损伤会一直延续至成年期，即使后来转为标准健康饮食也无法完全消除。 (0:00) 药用 GLP-1 受体激动剂可将循环中的 GLP-1 水平提升至生理基线的数千倍，从而平息食欲和“食物杂念”，但新型类似物究竟在多大程度上穿过血脑屏障还是通过外周迷走传入神经发挥作用，目前仍有争议。 (2:33) 饮食诱发的记忆损伤直接由肠道菌群改变所介导；高糖饮食会增加肠道副拟杆菌（Parabacteroides），而热处理饮食会消耗乳球菌（Lactococcus），临床前模型中粪菌干预可逆转这些认知缺陷。 (40:00) 自愿性体育锻炼是一种强有力的功能恢复机制，能够逆转由西方饮食引起的海马体记忆缺陷。 (47:04)

Neurobiologist Dr. Scott Kanoski and host Andrew Huberman discuss how nutritional inputs regulate hippocampal memory, gut-brain communication, and appetite control. Kanoski's preclinical research demonstrates that high-sugar and Western diets can cause enduring cognitive deficits mediated by gut dysbiosis, while natural satiety relies on intricate vagal signaling rather than simple caloric balance. Diet Quality, Gut Dysbiosis, and Hippocampal Vulnerability (33:42) In rodent models, juvenile and adolescent exposure to a Western diet (roughly 35% calories from fat, 15% from refined sucrose) or an 11% sugar solution produced selective hippocampal-dependent memory deficits. Notably, these cognitive impairments endured into adulthood even after animals returned to healthy diets. Kanoski's group linked this damage directly to the gut microbiome: sugar intake doubled the abundance of the genus *Parabacteroides*, and transferring these bacteria to control animals induced severe memory impairments in the absence of sugar. Similarly, an experimental diet containing advanced glycation end-products (AGEs) from heat treatment eliminated beneficial *Lactococcus* bacteria; reintroducing the strain successfully rescued memory performance. While prospective human cohort data link midlife metabolic dysfunction to elevated dementia risk, Kanoski noted that dietary quality is not deterministic. Clean eaters can still develop neurodegenerative disease, whereas less disciplined diets do not guarantee decline. Physical exercise acts as an effective countermeasure in rodent models, rescuing diet-induced hippocampal memory deficits through both central nervous system adaptations and systemic metabolic improvements. Vagal Gut-Brain Circuits and Hippocampal Memory Encoding (76:45) Ascending projections of the vagus nerve serve as a primary information highway from the viscera to the brainstem. Gastric mechanoreceptors detect physical distension, while intestinal chemoreceptors monitor nutrient composition and osmolarity. Kanoski's laboratory traced these visceral signals ascending to medial septum acetylcholine neurons, which directly innervate the hippocampus. Using fiber photometry, his team demonstrated that hippocampal acetylcholine spikes during food consumption and accumulates in a postprandial staircase pattern, priming the brain to encode the spatial and environmental context of the feeding experience. Disrupting this vagal conduit impairs cognitive function. In preclinical studies, lesioning gastrointestinal-innervating vagal fibers triggers distinct hippocampal memory deficits. Kanoski and Huberman highlighted clinical parallels in 20th-century medicine, where truncal vagotomies were routinely performed to treat peptic ulcers; longitudinal data from Taiwan later revealed a positive correlation between these surgeries and an increased incidence of dementia. Endogenous GLP-1 Signaling versus High-Dose Agonists (2:33) Naturally produced glucagon-like peptide-1 (GLP-1) acts largely as a local paracrine signal rather than an endocrine hormone in bulk circulation. Enteroendocrine L-cells release native GLP-1 onto adjacent vagal sensory terminals to promote within-meal satiation. Rodent experiments led by Wolfgang Langhans established that severing sensory vagal connections or knocking down vagal GLP-1 receptors abolishes native GLP-1's satiating capacity, causing animals to consume significantly larger meals. Conversely, clinical medications such as Ozempic and Wegovy deliver super-physiological doses thousands of times higher than natural levels. Kanoski noted that whether modern synthetic peptides cross the blood-brain barrier remains debated due to fluorescent imaging artifacts, though they heavily access circumventricular organs. Addressing patient trends, Kanoski emphasized that no formal clinical trial data support "microdosing" to curb side effects or preserve appetite. Furthermore, because most clinical patients discontinue GLP-1 therapy within two years due to nausea, vomiting, or cost, sustained metabolic health still requires nutrient-dense diets and resistance training to preserve lean mass. Cognitive Satiety, Sweetener Ambiguity, and Oxytocin Networks (26:50) Internal appetite cues are strongly governed by episodic memory. Human psychophysics studies, such as Suzanne Higgs's biscuit priming trials, show that vividly recalling a recent meal substantially suppresses subsequent food intake. In Jeff Brunstrom's deceptive soup bowl experiments, actual swallowed volume dictated fullness immediately after eating, whereas the visually remembered portion size determined subjective hunger two to three hours later. This coupling between sensory cues and metabolism is central to the debate over non-nutritive sweeteners. Preclinical models indicate that decoupling sweet taste from caloric intake impairs anticipatory cephalic phase insulin responses, yet Kanoski cautioned that human clinical trials remain contradictory, preventing clear prescriptive guidelines. Finally, neuroendocrine signaling produces divergent feeding effects: paraventricular hypothalamic oxytocin projections to the brainstem suppress meal size, whereas Kanoski’s group discovered that hippocampal oxytocin receptor signaling is required for the social facilitation of eating, wherein animals consume larger meals in the presence of familiar peers. A persistent methodological limitation in nutritional neuroscience is the healthy baseline of laboratory controls, which makes cognitive enhancement difficult to detect compared to diet-induced deficits. While animal models demonstrate that specific bacterial strains and vagal signals causally alter memory and meal size, human clinical data remain ambiguous regarding the long-term cognitive impacts of non-nutritive sweeteners, ultra-processed food classification, and super-physiological GLP-1 therapies.

[13:24] Dr. Scott Kanoski: one instrument in that symphony [20:00] Dr. Scott Kanoski: trick the wisdom of the body [25:00] Dr. Scott Kanoski: I consume Coke Zero regularly... It tastes great. [37:15] Andrew Huberman: If I took a carrot and I just ate it, most people know what that tastes like. But if I took that carrot and I sliced it and basted it with some butter, maybe a little bit of olive oil, some salt, and I stuck it in the oven and cooked it until it was soft... It has almost like a meat-like quality to it... a little tangy, but savory. [50:00] Andrew Huberman: medicine loves to start with a sledgehammer [70:00] Dr. Scott Kanoski: any weight loss program... should have some nutrient and physical activity components embedded in that program. [72:54] Andrew Huberman: a song, not a gong. [76:45] Dr. Scott Kanoski: Where am I? Can I get back here and do this again? [81:05] Dr. Scott Kanoski: symphony of chaos [103:39] Scott Kanoski: common brain currency [116:43] Scott Kanoski: social facilitation of eating

[0:00] When I started studying how diet impacts neurocognition and memory function, the first model we were studying was a high sugar model. The animals basically had ad libitum access to a sugar solution about the same percentage of calories as a soft drink that we consume and otherwise they had healthy food and water. With this model, the animals show hippocampal-dependent memory deficits when they're older, and these seem to persist later into life even though they're not consuming the sugar anymore. There may be a role for the microbiome. There's some changes in the bacteria in the gut from the sugar model that may have a functional connection to the memory impairments. We've also looked at models where the animals are consuming... like a total junk food diet. So we give them chocolate peanut butter cups, ruffled potato chips, rodent high fat, high sugar diet. They show these memory impairments that last, even after you switch them to a healthy diet. Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Scott Konosky. Dr. Scott Konosky is a professor of human and evolutionary biology and neurobiology at the University of Southern California. His lab studies how hunger and memory interact and how the mind and body impact appetite, body weight regulation, food craving and choice. Dr. Konosky's lab also studies how different types of nutrients impact brain development and brain function later in life. Today we discuss many topics including GLP drugs, how they work, how they impact hunger and how they impact things like longevity, cognition and drives in general. about how your brain and body control your relationship to food. And today he shares that knowledge with you in a clear, unbiased, and in many cases, actionable way. It's a conversation about the interactions that occur between your brain and body involving hormones, neurotransmitters, your memory, and your experiences that I'm confident will powerfully inform how you think about food, your food choices, and nutrition in general. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my conversation with Dr. Scott Konosky. Dr. Scott Konosky, welcome. Thank you. Pleasure to be here. Thanks for the invitation. You work on a topic that people experience every day, which is hunger, feeding, and hopefully satiety. But we also have this obesity epidemic, which seems to be partially mitigated by the GLP drugs. But there's a lot to this whole thing that we call hunger and food and appetite and weight and all of that. And today, you'll educate us about all of it. But to start things off, because it's on everybody's mind, What are the GLPs? What is this glucagon-like peptide one in its natural form in the body? And then perhaps we can talk about the drugs that increase their levels because... Either everyone's taking one of these now coming off of one of these now Thinking about taking one hates the idea that anyone's taking them or is has someone that they know is taking one. GLPs are here. In its natural form, it's an incretin hormone. So it's secreted from the distal intestines around food ingestion. So there's a little bit of secretion before the meal actually starts. Then there's additional secretion during the meal. And this gets into circulation. GLP-1 message throughout the brain. What do those do? Are they related to hunger as well? The peripheral GLP-1 and the central GLP-1 have very similar effects. So they're involved in hunger suppression, but they seem to be operating independently. So there doesn't seem to be a strong connection between the peripheral GLP-1 physiological system and the neurons that make GLP-1 in the brain. But they do both have appetite suppressing effects. But presumably they're doing other things as well, right? Yeah, they're helping to regulate blood glucose levels, to stimulate insulin secretion when there's high levels of glucose present in the blood. In fact, the first application of GLP-1-based drugs was for diabetes treatment, not for obesity. But because they also suppress appetite and food intake, which leads to body weight loss, now they're probably more widely known for their weight loss capacity present day. as diabetes treatment. My understanding is that the GLP-1 drug [5:00] Hugs. So Ozempic, Wagovi, and on and on, that they increase levels of GLP-1. Thousand-fold more than we ever experience naturally. That's correct. Super physiological, for sure. Is there anything known about the potential... downside to that or upside. Well, I mean, most of what we know is an upside. I mean, people have been taking GLP-1-based drugs for over a decade now, and the clinical trials support the efficacy of these drugs. There are side effects, nausea and emesis, emesis being vomiting, the most common side effects, and this can lead to discontinuation in a lot of people. They kind of tolerate it for a certain period of time and then at some point discontinue the treatment. limitation of these drugs. It's trying to mitigate those side effects and to have more long-term efficacy beyond the initial weight loss. I hear that some people nowadays are taking far less than they are prescribed. So micro dosing, a term borrowed, obviously, from the psychedelics community in order to offset some of the side effects, still get some appetite suppression and perhaps also reduce their cost because some of these are quite expensive, although many are moving to generic forms. Are there any animal and or human data that you're aware of on micro dosing or is this just a natural experiment that people are doing? I'm not aware of any any data on that. Placebos are very effective, so there could be some of that involved. I'm old-fashioned, and I like to see the large clinical trials, randomized controlled clinical trials, before I start to believe something's actually working. And we just don't have those studies to date on microdosing. Seems like they probably won't be done. I mean, there's not really an incentive for the drug companies anyway to do it. People taking less, buying less seems like not a good business strategy. that anyone's doing that right now or that they will in the near future. So we're kind of left with anecdotal reports in that zone. I also hear about some non-weight loss, related benefits of the GLPs. In fact, I know people who are of healthy body weight who are taking quote unquote, micro doses, or even full doses in order to glean what they claim are some of the benefits on cognition, on energy. A friend who is diagnosed with chronic fatigue syndrome has been micro dosing it. And she loves the effects. She's working with a physician, obviously, she doesn't like the appetite suppression, because she's already very lean and a little, not underweight, but close to it. So, but it speaks to the possibility that taking or elevating unrelated to the weight loss. Absolutely. The receptor for GLP-1 is not exclusively expressed in regions of the brain that control appetite and food intake and glucose regulation. They're pretty densely expressed throughout the brain. And this is including regions that are in the reward circuitry in the brain, the mesostriatal pathway. There's receptors in the midbrain VTA, the striatum, nucleus accumbens. One of my favorite brain regions is the hippocampus, which has a lot of GLP-1 receptors. So there's definitely possibility of applications for these drugs or different GLP-1 receptor agonists for substance abuse disorder and potentially even memory disorders and dementia. And there's a lot of certainly preclinical data to support that. The clinical data are just ongoing and starting to come out now. And part of the idea with the applications of GLP-1 type suppression has to do with the capacity of these drugs to get into the brain. This is somewhat of a controversial topic in our field of research. The first generation of GLP-1 drugs, so 2005 to 2012, we collected some preclinical evidence in rodents suggesting that a large part of the mechanism of action for food intake suppression was through brain action. So the drugs would get whether these newer generation GLP-1 drugs like Ozempic, Wigobi, are getting into the brain is less clear. Really? Again, controversial. So some studies will, mostly preclinical, exclusively preclinical, will tag the peptides with a fluorescent molecule and try to look at where it accumulates in the brain. And you see a lot of it clump into what's called the circumventricular organs, where there's no blood-brain barrier protecting the brain from the circulation. So there's a school of thought that these drugs are acting primarily in those circumventricular organs. But those studies are tricky because fluorescent molecules fade, and the brain has autofluorescent signal. So we could be missing [10:00] something with those fluorescent studies. There's better ways to do this, but it's expensive and complicated where you radiolabel the peptides with like carbon-14, and you can actually determine if it's getting into the brain and where. Those studies, Elizabeth Rhea, Bill Banks, and colleagues at the University of Washington are starting to do some of those. And it looks like some of the early generation of GLP-1 drugs readily get into the brain, and some of the newer ones less clear. Maybe it takes a little bit longer, but the jury's still out. Where they're getting into the brain is not something we have a clear understanding of at this point. I'd like to take a quick break to acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFASs or Forever Chemicals are still found in 80% of nonstick pans, as well as utensils, appliances, and countless other kitchen products. 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Helix Sleep makes mattresses and pillows that are customized to your unique sleep needs. Now, I've spoken many times before on this and on other podcasts about the fact that getting a great night's sleep is the foundation of mental health, physical health, and performance. When we aren't getting great sleep on a consistent basis, everything suffers. And when we are sleeping well and enough, our mental health, physical health, and performance in all endeavors improve markedly. in the quality of sleep that you get each night. How soft it is or how firm it is all play into your comfort and need to be tailored to your unique sleep needs. If you go to the Helix website, you can take a brief two-minute quiz and it will ask you questions such as, do you sleep on your back, your side, or your stomach? Maybe you know, maybe you don't. Do you tend to run hot or cold during the night? Things of that sort. You answer those questions and Helix will match you to the ideal mattress for you. For me, that turned out to be the Dusk, D-U-S-K mattress. for more than four years now, and it's been far and away the best sleep that I've ever had. If you'd like to try Helix, you can go to helixsleep.com slash Huberman, take that two-minute sleep quiz, and Helix will match you to a mattress that's customized for you. Right now, Helix is giving up to 27% off their entire site. Helix has also teamed up with TruMed, which allows you to use your HSA FSA dollars to shop Helix's award-winning mattresses. to get up to 27% off. I'm sort of veering us toward reward and reinforcement and memory, because even though those are topics that come up in the context of drug seeking, of pleasure seeking and on and on, in the context of food, you know, what we consider rewarding and what we crave are very closely related. And memory for what we think is going to soothe us is also, or satisfy us at the level of food is also seems to be a strong component. I know you've worked in these areas, but as a way of getting directly there, I'm very curious how the GLPs are actually suppressing hunger. If let's assume that take a full dose or a microdose of a GLP-1 drug, what is the sensation that people report? I've never actually taken one, so I don't know. Okay. So, but I hear, like, presumably it's satiety, but does that mean fullness? People will talk about reducing food noise in air quotes. What is this at the level of biology? So the... GLP one normal physiological GLP-1 that we secrete in the body likely has a paracrine mechanism of action. Could you describe paracrine? Yeah, so the vagus nerve innervates our GI tract, and there's receptors for GLP-1 on the terminal. So right where the nerve is contacting the gastrointestinal tract, there's GLP-1 receptors. And this paracrine mechanism is where the GLP-1 is released from these L cells in the intestines and immediately act on nearby receptor [15:00] that are expressed on the vagus nerve. So that's one mechanism through which GLP-1, both the GLP-1 drugs, as well as our physiological GLP-1, may be producing this feeling of satiation. So the vagus nerve communicates a lot of within-meal signals that contribute to us stopping eating. At some point, we get full. This process is called satiation. GLP-1 is a big player in that process. not exclusively through the vagus nerve, but probably largely through the vagus nerve, through this paracrine mode of action. So this sends a signal to the brainstem. That's the first site in the brain where the vagus nerve signals to that the animals had enough food at this point, the stomach starting to expand, there's nutrients entering the intestines, and there's sort of a symphony of signals that some act through the vagus nerve, some don't, but eventually lead to and meal termination. And GLP-1 is one instrument in that symphony. does it turn off the desire for food as well? Like people will talk about less food noise. And I know many people who are taking these drugs, some of whom are really bullish about also exercising, some who aren't. So we'll get to that a little later. But they all talk about reduced food noise, which tells me that before there was noise. And I don't... No, because I haven't asked them whether they were aware of that noise. So I'm trying to imagine, having never taken one of these, what that noise is. I mean, when I see blueberries, I want to eat them. But when I see bread or a steak or something, I may or may not want to eat them, depending on... when I ate last, time of day, this kind of thing. So what is food noise? I am not someone who experiences food noise either. So it is a bit of a strange idea to me. But I've certainly heard, same as you, anecdotal evidence of people who are taking GLP-1-based drugs and are saying that, wow, it really, really canceled the food noise. Whether that's based on receptor binding in the brain, in higher order brain regions that are involved in memory and cognition, hippocampus prefrontal cortex, We don't know. Again, I think that's one of the big gaps in this field is understanding where the drugs are acting. Are they getting to these regions in the brain that are involved in higher order cognitive processes that may mediate the food noise? Or is this basically just a gut vagus satiation mechanism? It's a lot to uncover in that area still. What's the evidence that the vagus nerve is? Crucial for the action of GLPs and suppressing hunger if you do a selective lesion to the the sensory or vagus nerve as it comes up from the GI tract to the brain and then inject GLP-1. It's not effective in In reducing food intake. Okay. The native GLP-1, not a long-acting GLP-1 drug, because that's a different story. They're in circulation longer, can get into the brain. But if you inject the short half-life native GLP-1 and the animals have a sensory lesion of the vagus nerve, they don't show the... The food intake reduction. This is work from Wolfgang Longhans in Zurich and his colleagues. They also knock down using short hairpin RNA interference so you can dial down the expression of GLP-1 on the vagus nerve. And those animals have a phenotype, right? So they eat more. Yeah, they believe is larger meals. Gotcha. So that's all consistent that our body is telling our brain when we've had enough because of fullness of the gut and the presence of enough nutrients have come in. I was going to get to this later, but I think now is the appropriate time given what you just said. Artificial sweeteners and low-calorie sweeteners are a really big... topic online There's some in my Yerba. I believe I have some as well. It's Stevia, right? So it would be a low-calorie, quote-unquote, natural sweetener, although there's some manufacturing to take it from a plant to like a drink or a food, but different than like sucralose, et cetera. Um, of course there seems to be three camps. One is the camp that believes that these things are terrible, that they alter blood glucose, they mess up the microbiome and that they, um, maybe even cause brain cancer. I mean, that people have made that argument about aspartame. Um, I'm not in that camp, but you, you will see people arguing this, the, uh, The second group seems to be the ones that just say, look, this is not, it's a non-issue that these are inert in reasonable quantities of consumption. And then there's the third group. which I think is quite a few people that kind of wonder like, well, it's quote unquote human made. And like, maybe this stuff isn't good. Yeah. What, [20:00] What is the evidence, the research on consumption of, let's lump them for right now, low-calorie artificial sweeteners on development of appetite, development of the brain, development of the system that you work on, and what does it tell us? This is a very controversial topic, and I don't think we have definitive answers to support any of those three camps. called there's a cephalic phase response where we're releasing insulin before the nutrients actually get through the GI tract just from the the simple taste of sugar in the mouth and so this is part of our metabolism right if you if this was a sugary drink you take a sip you would have some insulin being released to kind of prepare the body prepare the physiology for that perturbation in blood glucose levels and there is some evidence in preclinical animal models that if you disrupt the relationship between sweet taste in the mouth and the caloric consequences of consuming something that you can have perturbations in appetite, in glucose regulation, kind of like you're tricking the wisdom of the body, right? So sweet taste means calories are coming away, but now it doesn't. And there's not a lot of randomized clinical trials generally I won't get into all that, but there's no definitive evidence from the clinical trials in humans that it's good for or bad for weight loss. There's some evidence in either direction. In the preclinical animal model world, there's some evidence that if you give animals habitual evidence, Exposure to artificial sweeteners that this will will disrupt their capacity to metabolize sweet taste Later on and can potentially lead to increased appetite and weight gain interesting. So this is a Early life, daily exposure to artificial sweeteners. Yeah. So we've done one study in my lab and I can speak more confidently about that please we had animals who were in the juvenile adolescent stage of development this is um the period of life in which we've studied a lot in my laboratory in terms of dietary factors on adult cognitive processes And we gave the animals a little bit of artificial sweeteners to consume each day. And we kept it within the FDA's acceptable daily intake levels. So this wasn't necessarily a sledgehammer. It might be something equivalent of six of these a day, something like that. And they consumed it voluntarily. We didn't put it in the drinking water. This was something they liked. They would just get their daily dose and carry on. And when the animals were adults, we then tested it. neurocognitive and metabolic effects of having that exposure during development. So at this point, they're no longer getting the sweeteners. They're just consuming healthy rodent chow and water. And in this case, we found that the animals had some memory impairments, which was an unexpected finding. We don't really know the mechanism for that. But they also had some glucose regulatory changes as well. So if you infuse glucose and bypass the mouth, there's a spike and the animals that have this exposure showed a larger insulin spike. They also showed changes in the sweet taste receptor expression on the tongue. So we found some, changes. This is not like whopping sledgehammer effects, but at least in that model with rodents consuming artificial sweeteners daily during that developmental stage, there is potentially some impact on neurocognitive and metabolic processes when they're adults. Interesting good caveat is this is a rodent model sure um, but we did use Three different sweeteners and it didn't seem to matter which one we used to recall which those yeah, we had stevia mm-hmm ace K and and saccharine Saccharin is not one that's common in human beverages and foods these days, but it's one that rodents like quite a bit. So a lot of the rodent model artificial sweetener literature is based on saccharin. Okay. Thanks for clarifying. I always wondered. When I was growing up, saccharin was always on the table in restaurants. Sweet and low. Yeah, I think it's one of them. Yeah. And nowadays, stevia, aspartame, and sucralose seem far more common. that it's a preclinical meaning animal study. You mentioned before that you can find data that support the use of low calorie and artificial sweeteners for weight loss, as well as studies that contradict that. Is there any work that you're aware of that's going to try and reconcile this? Because I feel like they are everywhere now and I don't demonize them. Obviously not. I'm What's your thought on these? I mean, do you actively avoid them? I mean, you've had [25:00] a few sips of your drink. So apparently you don't avoid them entirely, but do you Would you, given the state of the evidence, recommend people take a step back for young kids consuming artificial sweeteners? You don't have to give a recommendation. I don't think we have the evidence for recommendations at this point. The literature is all over the place. And like you were alluding to a minute ago, I don't think that this is going to be solved anytime soon. There's not going to be a randomized clinical trial that's going to figure this out. and beverage consumption with habitual artificial sweetened Beverage consumption that that could have some beneficial effects on weight loss, but again, there's no reliable Trend line where you can say this this is good or bad. So I don't know which of the three camps that that puts me in but I consume coke zero Regularly. Yeah, it's good. Yeah, it tastes great. It tastes great. It tastes great. Yeah, so I guess then the takeaway from in my mind is it. people will have to decide whether they want to be in the experimental or the control group, given what they know. Right. Right. Yeah. Which is kind of the best scenario. People can know that the state of evidence is mixed. Yeah. And somewhat unclear. And then they can place themselves. And somewhat, you know, driven by preclinical models. So that's always that asterisk caveat. So – The memory system in the context of food. I'm fascinated by this because I happen to love what most people consider healthy foods, maybe to an unhealthy level. But I realize that some people have this relationship to certain foods where they just... accept that that food, however unhealthy, just needs to be a part of their life in some way. It's kind of interesting. It's kind of how I feel about caffeine. And I wonder if that's memory based. You know, if there's some association early in life or later in life and the food provides something beyond just comfort, what is the evidence that our memory of a food experience can play an important role in how we frame that food in our behavior? Our memory of eating a powerful effect on how much we eat subsequently let me just give you a couple examples so in one study from Suzanne Higgs and colleagues, they would have people consume a pizza lunch, and then they would have them come in a few hours later, and then they would prime them to really think about the memory of that pizza lunch in one group. Another group was primed to think about something else. I don't remember exactly what the other experimental condition was, but not that lunch. And there might have been a third control group that had no priming. And they were given, they call them biscuits in the UK, but we call them priming had an effect on how much They ate at the cookie. taste test. And if they were primed, to remember the lunch they had just consumed, they consumed fewer of these biscuits or cookies. So in general, the memory of recent eating... will contribute to eating less at the subsequent eating occasion. There's another interesting study by Jeff Brunstrom and colleagues where they had, I think it was tomato soup. So it was a bowl that had a peristaltic pump that was either putting more soup into the bowl or pulling it out. But the participants were not aware that that was happening. So they saw a certain volume of soup and they consumed the whole bowl, but that could have been a mismatch. It could be that they're seeing 300 and they're consuming 500 mLs or they're seeing 500, but they're actually pulling the soup out. So they're consuming 300. So this is a way to manipulate the memory of the meal. How much did you think that you, you consumed? So it's sort of a magic bowl of soup where I'm continuing to eat soup, but the levels are not going down. Yeah. Or that, or they're, or they're going down more than they would just by consuming it. And if you ask them to rate their hunger right after It didn't matter what they saw it was based on how much they actually consumed right so that that's sort of the wisdom of the body But then a couple hours later that that flips and their hunger ratings are more Driven by what they saw what they think they consumed versus what they actually consumed Interesting. Yeah, in fact read to me really interesting because you said like the wisdom of the body piece is great like you've eaten Till you're full, till you're satiated. But then you said the memory of how much one thought they consumed – impacts what you eat uh i don't think the study actually had them eating after that this was a self-reported hunger rating got it but you know presumably it could extend how much you would eat at a subsequent meal? So much of it seems psychological. I think we've all experienced, like when we're really, really busy, I know there's some people who just seem to eat a lot more during stress, and some people, like their appetite just shuts off. They [30:00] - Forget to eat is what we say, you know, or they're too busy to eat. Is there any indication that people, into one or the other category, like people that forget to eat or people who eat when stressed. So we study how... Eating impacts memory systems we mammals when we evolved we didn't have food readily available right you had to compete for for food resources in a very complicated environment and a lot of the systems that are traditionally studied for their role in metabolism and appetite and satiation control actually have beneficial effects on promoting memories. And our view is that that makes sense because when an animal, encountered nutrients, this is a very important event for that animal. It would be advantageous to remember what was consumed, What were the consequences of that consumption? Can I find this food down the road in the future? And trying to remember where the food was located. So we think that these systems that are responding to nutrients when we eat are actually promoting nutrition. memory function. Potentially, this is a system that evolved because of how important it would have been to remember these eating occasions. These days, maybe less so in modern human environments. You can find a cafe, you don't need to remember exactly where everything is, it's relatively easy to get food. But we think that these satiation Systems are very much tuned into the memory systems in the brain and and our focus has been on the hippocampus I'm guessing that your students probably ask you this from time to time, which is, you know, when and what and how much should they eat in order to optimize brain function? That dreadful word, optimize, not one I particularly like, but I feel like it's highly individual. I'm most focused when I haven't eaten in a while, up to a point, and I'm thinking about food all the time. I guess that's food noise. And if I eat something... and I don't eat too much, I'm good. But if I eat just a bit too much, then I'm sleepy. Like, it seems like... energy and focus and memory and learning. I mean, it's kind of a narrow bridge to walk. Yeah. And as you pointed out, I think there's a lot of individual differences in this. I always ask my undergraduate class, how do you guys eat? I'm traditionally three meals a day, but some of them graze all day, never eat a proper meal. Some of them eat one meal a day. And I'd like to assume that many of these individuals sort of fall into what's a sort by their schedule and course demand. But yeah, I don't think there's one recipe for when should you eat, how many times a day, how much, what's the distance between eating and some kind of mental activity or cognitive demand. Yeah, it seems like it's worth doing some self-experimentation for people to, you know, I mean, my read of the data on intermittent fasting is that It's one effective way to lose weight, but people can also lose weight by eating. just eating fewer than maintenance calories across three or even more meals. Like I think for so many years we got excited that like there was going to be this magic solution to eating and weight maintenance. But one of the godfathers of obesity research is George Bray. He was asked and it was a chapter in a book, but he was talking about what's the right diet. I mean, this is when this was written. It was Atkins diet and Mediterranean diet and all these different diets. that The best diet is one that you can stick to, and that's going to be a different approach for different people. Let's talk more about the memory system because I'm intrigued by this. So you study not how memory impacts food intake but how food intake impacts memory. I would say we're on both sides of that. Okay. So let's talk about how food impacts memory. If I want my memory system to be as robust as possible, what should I avoid? Right? head injuries, you know, opiates and methamphetamine. I think we all agree on that those are bad for memory. When I started studying how diet impacts neurocognition and memory function, we were working with adult animals and we were using what we refer to as a Western diet. So this is a diet that maybe 35% of calories from fat, 15% coming from sugar, and a lot of that's simple sugar. So, you know, simple sugar carbohydrates, not complex starch carbohydrates. And that in animal models dependent memory impairments. If the animals are on this diet for even like a week, but generally these studies are take a few months and the Hippocampal-dependent memory processes seem to be more susceptible to the negative impacts of these dies [35:00] ...than other kinds of memories that don't rely on the hippocampus. So the hippocampus is somewhat of a canary in the coal mine. And when I started my lab at... Here in Los Angeles, we're looking at development. So shifting away from adult models and looking at if you give animals individual components of a diet during the juvenile adolescent phase of development, is there a longer term impact on their memory systems? And the first model we were studying was a high sugar model. So the animals basically had ad libitum access to a sugar solution about the same percentage of calories as a soft drink that we consume. And otherwise, they had healthy food and water. And with this model, the animals show... Hippocampal dependent memory deficits when they're older and these seem to persist later into life even though they're not consuming the sugar anymore. So we had a few studies with that model. Um There may be a role for the microbiome. There's some changes in the bacteria in the gut from the sugar model that may have a functional connection to the memory impairments. We've also looked at models where the animals are consuming... like a total junk food diet to try to look at mechanisms. But again, it's the same kind of thing. So if the animals consume a junk food diet, so we give them chocolate peanut butter cups, ruffled potato chips, rodent high fat, high sugar diet, they show these memory impairments that last even after you switch them to a healthy diet. That's not to say that we couldn't reverse these memory impairments with some kind of other intervention other than just putting them back on a healthy diet. But at least in rodents and during this developmental window, these kinds of foods have a long-term impact on neurocognition. We have a preprint, which is not a peer-reviewed publication yet. It's sort of in the process of becoming that, hopefully someday, where we were – trying to look at food processing from A mechanistic. individual variable perspective. So in food processing is a term we all hear, alter processed foods. The way this is studied in humans is there's this Nova classification system where you have four different categories of food processing where the alter processed food is basically just, you know, shitty food and then The other end of the extreme is, you know, perfect raw vegetables and completely unprocessed food. And That's not really mechanistic in terms of what types of processing it is. Matter? Because food processing, there's a lot of processes that happen to food in modernized food industry. So we wanted to try to take it one variable at a time. ended up heat treating the food. So this is an otherwise healthy food, and we baked it for an hour at a high degree, high temperature. And the idea behind this is that it induces something called the Maillard reaction. The Maillard is used in cooking because it enhances the flavor of food. So this is something that we do for a reason. This is a chemical reaction that happens depending upon the nutrient composition, the pH, a lot of factors. But when you heat treat food, just describe the subjective experience of it. Like if I took a carrot and I just ate it, most people know what that tastes like. But if I took that carrot and I sliced it and basted it with some butter, maybe a little bit of olive oil, some salt, and I stuck it in the oven and, um, cooked it until it was soft to come out. It has almost like a meat like quality to it, taste, um, that, um, it's a little tangy, but savory. Um, is that, that's what you're referring to. Yeah. Yeah. I mean the, the actual flavor, uh, components that are a result of the Maillard reaction are not well understood. So we can't point to certain flavonoids and say, oh, this is making it taste like this. But in general, you know, if you bake a casserole, it's going to taste better than before you baked it, right? Yeah. So we were trying to create this chemical reaction in otherwise healthy food. And what happens when you eat this food up is there's chemical byproducts of this process. They're called advanced glycation end products. The acronym is AGE, AGES. And these chemicals are actually in our normal physiology. So we have AGE circulating. receptor. And this system is generally associated with diabetes and aging and things that we don't think are great, great things. And when you heat food, depending upon the chemical composition of the food, the temperature, etc., you get these AGEs that are introduced into the food itself. So we're basically looking at if animals consume this age-enriched [40:00] I had is what we were calling it. During development, is there an impact on cognitive processes when they're adults? And it turns out, again, just the caveat is this is unpublished work, but preprint, is that we see memory impairments with this Asian-rich diet. We think that there may be a role for the microbiome. There was a population of bacteria that was eliminated through the heat treatment process. And when we reintroduced it to the animals, we were able to reverse these memory impairments. memory impairments. Could you describe the type of memory impairment? And I'm not trying to review your paper, but are these big effects? I mean, they're obviously statistically significant, or you wouldn't be describing them the way you are. But just to frame in our minds, I mean, are these animals, can they remember where something was placed and come back to it later? Or is it sort of like getting into challenges with higher order memory? is we have a maze actually about the size of this table where there's holes on on the edge of the maze, and the animals are using visual spatial cues surrounding the maze to remember where things are located. This is a hippocampal-dependent type of spatial learning and memory, and we've done different versions of this, but generally they're trying to remember where food was consumed. So they crawl into a little tunnel, they eat a meal, and then the next day we ask them, do they remember where that tunnel is? We also do memory tasks that do not have to remember which objects they've seen and which locations before. It's kind of like a, okay, I've seen this object before, but if I haven't seen it in this new location, the animal will preferentially investigate that object. These are just some of the examples of hippocampal dependent memory tests that we use. In terms of effect size, it... That's a little bit tricky. I mean, I'm not saying that it's... the equivalent of having a lesion to that brain region. But in some of these memory tests, you have above chance performance, and then you have not that. And generally, we see the control treatments will have above chance performance, giving us some indication that the animals remember above chance where that food was located or which object they've seen in which location. And with some of these diet manipulations, the animals are performing basically a chance. So they're not showing us any evidence that they remember where they got the food from before. All right. I'd like to take a quick break and acknowledge our sponsor, AG1. I'm excited to share that AG1 has just launched their newest formulation, AG1 Pro. AG1 Pro takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnosine. 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If you would like to try AG1 Pro, you can is giving away a free bottle of omega-3 coenzyme q10 with your first subscription again go to drink ag1.com slash huberman to get a free bottle of omega-3 coenzyme q10 with your first ag1 subscription I don't want to make too much of the findings, nor do I want to place you in the position of feeling like you have to, but I'm intrigued by this process. because for the last five years or so, there's been this unofficial naming of Alzheimer's, like dementia, as type three diabetes, which I know drives certain physicians and neurologists absolutely bonkers because that's not an official diagnosis term. But I think we do, on the other hand, now well appreciate that diet impacts the brain and that really disrupted metabolic function. chronically elevated insulin due to elevated blood glucose from either food intake or otherwise is problematic for the brain. And as a consequence, a lot of people in the spheres that I find myself in these days are are trying to offset their potential memory loss in the future, or even treat the memory loss of their parents or spouse by saying, hey, look, at a minimum, we can control food intake. It might not be a cure, but... Some are trying ketogenic diets, for instance. Some are trying to manage blood glucose using metformin [45:00] or berberine, neither of which I do, I should be clear. Some are taking even more aggressive measures. And now there's the discussion about the GLPs, it's like maybe these will improve longevity of brain function or improve memory. So I don't think it's too much of a leap to just chop it up around this topic and just With the caveat that you're not talking about specific data, what are your thoughts on this, this notion that maybe some major component of age-related dementia, maybe even Alzheimer's, is not? earlier in life or current food intake related. Yeah, there's pretty strong evidence from perspective studies. I mean, there are correlations, but from perspective studies showing that midlife dietary patterns and metabolic status can be associated with an increased risk of dementia later in life, including viscerative paucity. So the connections appear to be there. In animal models, we have transgenic models of Alzheimer's, where animals have gene mutations that lead them to... at a later point in their life, develop symptoms that are analogous to human Alzheimer's. And in the preclinical world, there's evidence that consuming a Western diet, so again, a high percentage of calories from fat and simple sugars can exacerbate that pathology, can essentially lead the animals to develop the symptoms of that Alzheimer's in this transgenic model earlier than they would if they were consuming a healthy diet. So the connections are there. I think it's more prospective than something you can deal with once symptoms arise. I don't think that I think it's it's more important to have a healthy dietary pattern throughout life as opposed to once there's a problem, you know, switching, switching at that point. Yeah. So it's sort of the and here I am heavily. Yeah. joking slash stereotyping. It's sort of like, were you raised in West Los Angeles where everyone's talking about eating healthy all the time? It's like a major topic of focus. Are you from an area like, um, an area of the country where nutrition isn't prioritized? Or are you sort of like most people where you grew up eating some healthy foods with a mix of some ice cream and pizza, and a little bit of alcohol for most, you know, like, I mean, most people are in this kind of mishmash, and yet we see people with Alzheimer's who are dealing with metabolic dysfunction. And we see people who get Alzheimer's who otherwise look healthy. I don't see how we can draw a one-to-one correlation between food. No, we definitely can. Yeah, there's... correlations, but it's not a direct line. It seems these days that People just... feel really good talking about the fact that exercise is one of the few things we can do to maintain or improve brain function. I'm not aware of any studies showing that exercise actually makes people smarter. I think it is places the body and brain in a position to go... learn and get smarter or to hold on to what they've got. But the question that I'd can't seem to find an answer to is are the positive effects of exercise on cognition and memory are they the consequence of improved metabolic function end of story or is there something else there i think the answer is probably both um getting back to this this diet model in rodents where we have a western diet there is some evidence that exercise can reverse those those memory deficits and in part that's happening through changes in the brain interesting so for fed an unhealthy diet, let's just call it, and then later are put on a healthy diet and exhibit these longstanding memory deficits. If they exercise, they can rescue those deficits. That's been shown in rats, yeah. Interesting. And I recall, it never worked in this area, but that one could do a memory test where you actually have the animal's swim to find a platform horse water. So does the exercise have to be related to the memory task itself, or can they just run on a wheel and that rescues their memory? Well, There's treadmill models and there's wheel running models of exercise in rodents. One of the reasons that we don't use the procedure you were talking about is it's stressful for the animal. They don't like being thrown into water and there's a physical demand to swim. And so we try to avoid that particular task where the exercise capacity of the animal has any input at all into their performance. We're talking about here sits right at the edge of like where modern brain health is. and longevity care is at. It's like, on the one hand, we're talking about like what one eats, whether one exercises and brain function. But to my knowledge, there's nothing else. known about [50:00] Alzheimer's that tells us to do something specific besides also trying to be a lifelong learner and social connection. Okay. Those are critical too, obviously, but there's tons of stuff. It seems that can impair the system, but we actually have in hand very few things besides exercise, quality nutrition, social connection, and an ongoing curiosity to try and maintain brain function. I realize this isn't your specific area of focus, but when you look out on the landscape of dementia and alzheimer's research pre-clinical or in humans what like you've spent some time in the hippocampus as a researcher like do you think we're going to get to the place where what we call alzheimer's is is a reflection of a bunch of bad choices plus some genetic pre-loading of the system um some susceptibility that might be heightened in some people or do you think there's really a disease that is independent of all that. We haven't come very far in terms of finding effective treatments for Alzheimer's, as I'm sure you know. And one thing that we've been doing in my lab is to try to think outside of the box and try to think about how the gut might be connecting to this pathology as opposed to just looking at what chemical processes are changing in the brain one example of that is we done some work with with the vagus nerve i think i mentioned earlier and if you lesion the vagus nerve that as it's coming out of the gut the gastrointestinal innervating components of the nerve animals show hippocampal dependent memory impairments So there's a connection between the vagus nerve and the hippocampus, and we're interested in trying to understand, is that connection relevant to Alzheimer's and dementia pathology? We don't know yet. There was one study in a population in Taiwan that in the 1980s, maybe a little bit into the 90s, people would get vagotomies. So they would get a truncal vagus nerve lesion for stomach ulcers. That was a somewhat common treatment at the time. Medicine loves to start with a sledgehammer. Start with a sledgehammer. You got ulcers. Let's give you a vagotomy. Let's cut off the nerve. Let's cut the major connection between the brain and body. And it was effective for that. Yeah But what what interesting is we have in other countries not so much the US they have impeccable medical records that are kept for decades And you can look at OK if an individual had a truncal vagotomy for stomach ulcer what the probability of developing dementia later on And there does seem to be in one small study, a positive correlation. So there may be some risk factor for vagotomy in humans and developing Alzheimer's of some kind, some kind of pathology later on. We're interested in looking at that in a different cohort in the Swedish National Registry, looking at whether we can kind of dig in a little bit deeper and find out whether there's any risk in humans of having vagus nerve disruption and Alzheimer's pathology. In animals, we can study this a little bit more directly. So we have a transgenic Alzheimer's model in a rat. So they basically develop the amyloid and tau pathology in the hippocampus in an age-dependent fashion. So when they're older, pretty decent model as far as these things go. And we have devices that are called vagal nerve stimulation devices, and we can implant them. There's different kinds of VNS devices. The one that we working with it relies on mechanical distension and contraction of the stomach so it basically sutured to the stomach and it only sends a stimulation electrical stimulation to the nerve when the animals are eating, because that's when you get the natural expansion and contraction of the stomach. And we're interested in knowing whether these devices can, I don't want to say, eliminate the Alzheimer's pathology, but potentially improve the outcome in these animals. That's something that's ongoing. Right now, we have shown that these devices can rescue the memory impairments from an unhealthy diet. So we think there's some kind of functional benefits, potentially, of vagal nerve stimulation in models of memory impairment, but still in the baby stages of trying to figure that out. I can make up a simplistic story in my mind that I'm sure is only partially true, if at all. But I go something like this, that the memory systems of the brain, which clearly involve the hippocampus, that's not debated, evolved first to keep us alive as opposed to make us remember, you know, sweet memories from first junior high school dance, because that was really awesome. I'm just kidding. And that nothing is more fundamental to survival than our ability to keep ourselves [55:00] nourished and hydrated from day to day so that a huge component of our hippocampal function is is nested in our gut's ability to communicate with our brain. Hey, these nutrients came in at this timing and this amount, in the context of a bunch of other things like i feel like most neuroscientists would agree and you work on this system so i think am i on solid ground there yeah okay and not just the vegas nerve either we say the vegas nerve but also if you look at at hormones that involved in appetite and metabolism that get into the brain like insulin and ghrelin. There's a lot of receptors for these hormones in the hippocampus. So that seems to be an alternative pathway through which the hippocampus is getting insight into the metabolic state of the animal through these circulating humoral signals like leptin is another one that gets into the brain from circulation. It's really receiving the the the neural connection from the vagus nerve, but also the humoral sort of longer term energy status connection from these hormones. It's similar in many ways to the hypothalamus in terms of the receptors that are expressed there. And of course, the hypothalamus is the classic feeding center in the brain. That's where these AGRP palm C neurons are that I know you've discussed previously. That's the traditional feeding center. But We've been for a number of years now, been making a case that, hey, the hippocampus is really important for this, too. And feeding, eating appetite is not a reflexive response. It's very complicated. It's a very complex decision that has to be made when an animal decides whether to forage, where to forage, you know, what to eat. These are not not simple behaviors. mediated by these brain substrates that are thought to control more basic homeostatic regulatory processes like the brainstem and the hypothalamus, but you also have these higher order inputs that are very much tuned into this behavior as well. So here's the model I'm sort of simplistic model I'm coming up with in my head that the hypothalamus has these switches, find food, eat, stop eating, eat, et cetera. And we pretty much know what those switches are, the location of the neurons and so on because of the work of... Yeah. you and excellent colleagues in the field. And then there's this other system that we've been talking about that's a major topic of focus, this body-to-brain, vagus-to-hippocampus kind of memory system. And it's so interesting that... When an animal... or a human doesn't eat well, meaning enough food, So macronutrient, sure, most people are getting enough macronutrients, at least in this country. I realize there are exceptions, but not enough micronutrients, not enough of the essential fatty acids, the vitamins and minerals, the protein relative to the calories they're taking in. When that ratio is skewed in the wrong direction, then the memory system suffers. And so... if we... adhere to the adage, use it or lose it, right? I kind of am getting this picture after all these years in neuroscience that like our brain develops and our parents and we do as well as we can. we don't control everything at the beginning, and then we do that as well as we can, then we sort of land in this early stage of adulthood of like mid-20s, 30s, and then... Our goal is to hold on to what we have and improve on it if we can, right? I mean, there's nothing... you know, knew about the statement I just made, but that the gut is constantly updating, like, The body is getting what it needs. Therefore, if you're a neuron in the hippocampus, you can basically stay functional and alive. Otherwise, it sounds like neurons start cashing out. They might not die entirely, but I mean, this is a different picture of nutrition that I think is so important. And I think it fits well with what we're. learning about dementia and Alzheimer's that there is this blood sugar but also nutrient related to aspect to it. If this system from the body to the brain is really a core feature of keeping memory online and maybe even making it better without feeling the need to make specific recommendations. How do you personally think about this in the context of your own food intake? Is it like, okay, eat well, but not too much. We know that. But what do you think about doing that could keep this system robust? Because presumably you want to do that. I realize, and I want to be very clear, I'm not asking you to make recommendations, but you're more versed in this perhaps than anyone I've ever spoken to about this body brain connection as it relates to memory and food so I'm just curious where your mind is at and bracket it as many times as many caveats as you need to feel comfortable but I'm curious and I'm certain many other people are curious yeah I don't make specific recommendations about what people should or shouldn't eat. [60:00] But I do share our results with people who have kids who may be thinking about, you know, what do I feed my kid? And I always make the very important caveat that we're studying rodents. We think are a good model for memory systems, for energy metabolism. They are a good model for humans, but it's a very important caveat. That said, there is evidence in humans that supports some of what we are doing in rodents. colleagues did some studies in healthy adults. So this is undergrad students age approximate, and looked at their habitual dietary patterns and then how well they did on hippocampal dependent memory tasks. So these otherwise healthy adults are not diabetic, really just normal, healthy young adults. There was connections between habitual sugar consumption and saturated fatty acid consumption and how well they did on these memory tests. That's not to say that these a healthier diet. But I do think it's worth looking into what we know in humans, which is very little because humans, unfortunately, aren't that good at reporting what they actually eat. This is a major limitation in doing these kinds of studies with rodents. We control what they eat. We measure it. We have a hundred percent, near a hundred percent accuracy of what they're eating and how much. Even with phones nowadays where all they have to do is take a picture. It's improved it. Yeah. Is it that they lie or they're just too lazy or they? I don't, I don't want to say it's it It's just not an accurate process to date. I think having the apps... Involved they're gonna make it a little bit better. There's caveats with both the animal model research because the rats and the human Research because we don't have a lot of control about what they're eating and how accurate their reporting is but that said there there does seem to be Evidence in humans to support what we're doing in in rats. So I guess that not making precise dietary recommendations, but excess sugar, not good. Excess saturated fatty acids, not good. I wonder why... We've gotten so good at process creating quote unquote highly processed or even partially processed food that's designed to taste really, really good. Yeah. So people consume more of it independent of its micronutrient and other value. Why can't we engineer foods that have robust amounts of micronutrients. I just think this would be a great thing. And parents want their kids to be healthy and adults want to be healthy. I don't think anyone wants to feel sick. Yeah. provided, um, It was safe. I would love to eat a bowl of blueberries that had like 10 times as many polyphenols. I would... Pay more for those blueberries. I don't know how much more. I guess it would kind of depend. But... It seems that the engineering can be used to push the quality of food in Either direction and I don't understand why this isn't happening and people will say oh because they just want you to buy more and more Okay, that's true, but you can still keep food tasting good very good in fact so why aren't people engineering better, more nutritious food. As you're alluding to, I think the technology is there. I think it's just the sea change hasn't happened in terms of where the demand is, where the production is. I'd like to think that a sea change is possible. I mean, the food industry is over 60% of calories that Maybe not you or I, but many people consume... come from all to processed foods in the U S so that that's a lot over 60% and that's a direct product of largely that the food industry producing these kinds of foods, what you're saying sounds great. Like if there's a sea change in demand or some other top-down regulatory change in the food industry, yeah, I think that's certainly an optimistic perspective. Because even if people aren't eating enough fruits and vegetables, if you can spike an otherwise unhealthy diet with like – two pieces of fruit a day and one vegetable, which is not what, you know, sufficient. But if you overload those with more micronutrients, it just seems so straightforward to do. Yeah. I mean, clearly the ultra processed food industry has hacked the get people to desire more piece, as well as the marketing piece to drive it through like cartoons and clever marketing and celebrity marketing and this kind of thing. It just seems obvious to me now. There's also an issue. And I'd love your thoughts on this in the, in the science field itself. I mean, years ago, Thank you. I occasionally come across an article in the Journal of Neuroscience, which... you know, back then, I think still now as a respectable journal, it would be like blueberry intake correlated with improved cognition in rats. You'd occasionally see that. But I noticed that that kind of work got pushed aside. There seems to be more of an emphasis on finding relationships between the bad stuff and deficits. [65:00] Which I think is essential, but I feel like it's… I'm very much guilty of that, too. Well, and no, I think it's important work, but I feel like loss of function and sort of Well, gain of function is kind of a loaded term now, but it just means like things that Push things potentially in the other direction. I think part of the problem with what you're getting at in the preclinical world is – A standard rodent diet is very healthy. This is like 10 to 15 percent of calories from fat. The carbohydrate source is complex carbohydrates. So we're kind of starting with an incredibly healthy baseline. That's not to say there's not more room for looking at certain extracts, supplementation, and whether they can have beneficial effects. But with the standard rodent diet, the animals are... Hmm. They're not showing memory impairments on that. Some make sense. It's sort of easier to make something go wrong. Yeah. Then to take an already healthy baseline and and improve upon it. Yeah. I mean, I think it's I'm not going to blame science for this, but I feel like in some ways that's what led to this proliferation of like diet books. And this is the way to make your brain healthy. This is the way because there was just. there was a lot of empty space for people to step in and there didn't need to be any kind of formal structure that they had to obey. So in some sense, it's like, the landscape was perfect for that. Yeah, absolutely. Lacking a strong scientific literature in this area, Anything goes, right? Right, right. Because I think by now we all know what we shouldn't do. Yeah. Many people try not to. There's also, I've been reading about this, that with the advent of the GLPs, we are entering perhaps the first time in nearly 75 years where we might start to see thiamin deficiencies and micronutrient deficiencies in a fully modernized culture. Because people aren't eating enough. And when they are eating, they're saying, oh, you know, I'll just have like a little bit of this donut. I'll have a little bit of this salad. And, you know, salad is... most places doesn't actually provide that in nutrients, but probably the salads that you make or that you can buy at a really good market. Um, you know, but if you look at like most salads, there's a couple of people, pieces of iceberg, less like slices of cucumber, tomato, like that's not, that's not what we're talking about when we're talking about getting sufficient fiber and vitamins and minerals. Right. So it could be that we end up with a, a large, uh, population of people who are kind of skinny fat because of the loss of muscle with the GLPs, they're not exercising plus micronutrient deficient. And in terms of hippocampal function, it seems like that would be maybe as bad as obesity. That's not a concern that I have, but part of the reason for that is that – People don't take, in general, they don't take these GLP-1 drugs for a long period of time. A majority will discontinue treatment within two years of starting. Because of side effects or cost. Because of the side effects. Another reason for discontinuation in elderly populations, there's lean mass loss, which is, I'm not saying that GLP-1 drugs preferentially reduce lean mass. I'm not saying that at all. But when you lose weight, you lose both fat and lean mass. discontinuation but people just aren't staying on these drugs long enough to really have I mean to my knowledge there's never been micronutrient deficiency issues in any of the clinical trials which I That's most of what we know is from those clinical trials. Those are about a year or two, as I recall. Yeah, typically. But... Those trials are done in... individuals, everything's controlled, the diabetic and or obese. Now it's a whole new world out there where people can get their hands on these that don't need them. So I think there are a lot of potential issues with... GLP-1 based drug use in lean individuals that we just don't have any grasp on because we haven't We haven't done those clinical trials and probably won't. It's almost like a perfect storm. Like in a country, the United States, where healthy eating has never been a theme, if I'm honest. Yeah. You know, it's just not as some of you guys. A parent from South America, it's like... the foods they champion are healthy foods. Overabundance of meat, admittedly, in Argentina, but, like, the idea is, like, People from Eastern Europe will talk about, like, their comfort foods are often very healthy. Yeah. They have a lot of nutrients in them, like south of France and Scandinavia. And Americans will roll their eyes. They'll be like, you know, this, you know. But it's... It's a reality that, you know, Fried chicken, pizza, cotton candy, hot dogs, apple pie. These are like the American corn. These are the American foods. And so in the absence of a complete revision of how we think about food and health, I feel like What's needed more than ever is people need to be educated on what to eat to keep their brain healthy. One of the most common questions I get and I end up having to revert to exercise, sleep, and all the other stuff. [70:00] You can give answers, protein, fruits, vegetables. But my observation is that some people will do that. And many, many people are just they're looking for a pill or a solution. And the GLP seem to have provided a solution, at least to the weight piece. But it doesn't seem that they've provided a solution to the nutrient piece. And that has me... concerned frankly any weight loss program it should have some nutrient and physical activity components embedded in that program right simply taking a pill is not the optimal way to lose weight and the clinical trials where we have data from there is nutritional guidelines and physical activity guidelines embedded within those trials they are having them exercised most of them yeah i can't i can't say every single one but yeah I mean, this is one of the most Common sets of questions that I get around the issues we're talking about today. Just incidentally, like, should I be taking GLPs? Like, what about, you know, what should I eat when I'm taking a GLP? You know, can I microdose it? Can I go off it? What about the muscle loss? You know, it's like, I think this is the... going to be a major theme for the next five to 10 years. And that's an adult. So to say nothing of the questions about kids and GLPs, I don't know that there are any data on GLPs, drugs in younger populations. I'm sure there are, but I'm not aware of them. I'm not deeply familiar with them, but I believe that semaglutide may be FDA approved in some populations of teenagers, but I don't remember the specific parameters for that. I'd like to take a quick break and acknowledge one of our sponsors, Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium, all in the correct ratios, but no sugar. Proper hydration is critical for brain and body function. Even a slight degree of dehydration can diminish your cognitive and physical performance. It's also important that you get adequate electrolytes. 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Again, that's drinkelement.com slash Huberman to claim a free sample pack. Let's say that you had an enormous vault of funds to do research on anything in this system, or any other system for that matter. Have you ever played that experiment? It's just too painful to think about, given today's... It's a little painful. Unless you're offering the vault. No, but if you could... do any experiment here, like... didn't have to write a grant to do it. And you felt like, what would that experiment be? Like, what do you think is really needed in this field to start to really connect the dots or just that you think would be a fun, entertaining experiment? Because let's face it, scientists like to do experiments also for fun. In many ways, I'm lucky that we are Doing some of those experiments now like the example I gave earlier with the the vagus nerve stimulation device in this transgenic Alzheimer's model it that's what I want to be doing try to think about how how the gut might be Not just connected to the pathology, but potentially understanding that connection can lead to novel Treatments that haven't really been considered or applied before we are working on a what I would like to be working on, which is in some ways, it's a benefit of the NIH funding model that you have flexibility in what you study. Of course, you you put a proposal in and it's reviewed. And if you're lucky enough to get the funding, you're doing a lot of what you do. intended to do, but you're able to have a little bit of flexibility and, oh, we found this unexpected result, so we're going to go this direction with it. So, yeah, I think. I'm very fortunate to be doing what I want to be doing in the lab these days. I'd like to... know more about the nature of the signal from the vagus to the hippocampus. I mean, these days, most people who've heard of Vegas think about as a calming pathway. They've heard about humming or long exhale breathing, which is a different branch of the Vegas. That's, that's all still true about calming the body. But my understanding is that the ascending the from the body up to brain vagal connections are mostly excitatory. They are mostly about creating more arousal in the brain, not more calm and I think that confuses [75:00] A lot of people, but my friends who... do neurosurgery tell me that if a patient is, you know, maybe drifting under a bit, you can do vagal stimulation to make them more alert again. So clearly there's something there. So I'm curious what the nature of the signal from the gut to the brain is. Is it like we have food, we have nutrients, and that's sort of a bunch of gates. Like if you have enough fatty acids, enough protein, enough glucose, then three gates have to be open and then boom, there's a signal because the gut... Even for neuroscientists, we tend to forget that the gut doesn't go, hey, we just ate this amazing lentil soup. It's just the lentil soup has an effect and then electrical currents get sent up. And the signals in my mind are kind of crude. And so is it that then a bunch of... excitation is released in the hippocampus and now you can keep the neurons alive because excitation is good for neurons is that like kind of the picture it's not one common signal right so there's there's mechanoreceptors in the stomach and they're picking up on distension of the stomach when when food is in the stomach and that that's a vagal signal but that's distinct from chemoreceptors in the intestines so you get this um sort of different timing of different signals as the Just... unified electrical signal that's coming to the brain and these the neurons of the vagus nerves and the nodos ganglia, they express different receptors. They're very heterogeneous. They're not all the same kind of neuron responding to the same thing. We don't know a lot about What the signal is when it gets to the brainstem, but we do know that there's there's many different things that are contributing to that that signaling pathway So I don't think about it as just one unified hey, we've eaten. It's very nuanced. So it's a song, not a gong. Yeah, exactly. We've identified how this information gets to the hippocampus. So from the brainstem, there's an input to the medial septum. And then there's acetylcholine producing neurons in the medial septum are then innervating the hippocampus. So it's kind of a three-tier pathway through which the gut, at least from the vagus, this information is getting to the hippocampus. So acetylcholine is The currency that we've been studying most recently in this gut brain hippocampus axis. Interesting. Maybe we could drill into that a little bit because we had Michael Kilgard on the podcast who, if people haven't seen that, he trained with the Mike Merzenich, kind of like one of the modern granddaddies of adult adults. neuroplasticity and the data on increasing acetylcholine and the effects on adult plasticity to me still, after all these years, having spent so much time in that literature, are still kind of jaw-dropping. Like, if you get acetylcholine levels in the brain acutely elevated, you un-gate the incredible plasticity, which is not to say people should go to use nicotine. And by the way, if you're thinking about using nicotine, folks, if you use nicotine every day, you actually blunt the system, you reset the threshold. This is why it's... technically only a cognitive enhancer if used every once in a while. So like, I just want to put that out there because otherwise people will be looking up how to spike the system, but I'm really interested. So what is the, acetylcholine doing for the hippocampus when the gut sends this song of, hey, we've got these nutrients. What is the nature of that signal? So using fiber photometry recording, we can look at the activity of neuromodulators like acetylcholine when the animals are awake and doing something like eating a meal. Cool. And what we found is if you track the acetylcholine release into the hippocampus, when the animals are actively eating, so they're holding food, they're chewing it, ramping up when that's happening. And then when they stop, take a break, look around a little bit, starts to ramp down. And it kind of jigsaws like this throughout the meal. But one important finding is at the end of the meal, the baseline levels are higher than they were at the beginning. So it's like a staircase in some ways. It's kind of like up, down, up, down, but then eventually it's higher. We think that that elevated postprandial level of C. coli and hippocampus What the hell's going on? You know, like just ate this meal. Where am I? Can I get back here and do this again? That's definitely how I felt when I went to Portland some years ago and I had the best croissant I've ever had in my entire life, including in comparison to France. Yeah. And I have a memory map of how to find that place, assuming it's still there. It probably is. It was that good. It's probably still there. It was that good. And I don't consume that many croissants, especially not these days. But like, yeah, there's really something to it. get awesome taste, awesome, hopefully, nutrients also. It's like you collect your priors, [80:00] experiences leading to that. And I can see why that would be important for survival reasons, but I could also see why if this system was hijacked by highly processed foods, that, um, why we're so, um, in trouble nowadays and we we see the the same if the animal are eating healthy food versus like a high fat high sugar diet we see the same acetylcholine profile. So this really does have an analog to like TikTok scrolling versus reading a chapter in a challenging book or interesting story. Yeah. What's the thing you said that made me think of something you mentioned the taste and the nutrient? We don't see this with taste alone. So if the animals consume stevia, a non-nutritive sweetener, we don't see the acetylcholine release patterns in the hippocampus. So we haven't done it the other way around where we infuse the nutrients without taste. That's something that's in our queue to do in the near future. But my guess is that you need the combination of taste and post-oral nutrient sensing to drive this vagal acetylcholine signaling to hippocampus. How much is being done to really parse the... Dave. Character of the signal from the body to the brain, you know, the body brain connection some years ago was considered really hippy dippy. And now everyone talks about it. And the Vegas is the superhighway champion of this. body brain thing. We talk about in the context of breathing, meditation, trauma therapy, psychedelic therapies, learning, now food intake. And I get really excited when there's a repeating theme coming through on this podcast. When I sit down with experts like yourself and, and, So I'm wondering, especially as a person coming from the visual system where we can describe like, OK, when. Human sees a bar of light at this orientation of this intensity. We can trace the whole cascade now. That's a sensory system. This is a sensory system. Do we know what the nature of the signals are but unlike the visual system that Interoceptive awareness is a very messy process. You know, it's it's not a precise process. We can Discriminate between I'm extremely hungry or I'm extremely full but in between that this is very much unlike the visual system. These sensory inputs coming in are, there's some neural, there's some endocrine. It's like a symphony of chaos in some ways. I don't think we're ever going to get to the precise level of, at least, maybe I shouldn't say ever, but in the near future of really understanding the nature of that signal. The gestalt of that signal. One thing I... since i've been talking about the hippocampus a lot it seems to be where this interceptive awareness is being processed in the brain so give you an example if you take a human who's densely amnesic who has damage to bilateral damage to the medial temporal lobe including the hippocampus and these individuals have episodic memory impairments. So their memory span is between 10, 30, 40 seconds, depending upon the individual. And you have them eating food, they'll consume a meal, experimenter goes away, comes back with another meal, they'll eat the next meal. you And this will happen even a third time. They don't remember eating the meal. But what's always fascinated me about this situation Study and studies like this. I think Paul Rosin did the first one is that if you ask them to rate their hunger and satiety level like on a scale of zero to ten and They will be a 7 out of 10 after eating three meals. in a row. So of course they're getting this gut feedback to the brain. They're probably even feeling full, but they don't know how to interpret that signal. The hippocampus is needed to understand what that signal means. And there's analogous studies in rodents. Like if you do a lesion to the hippocampus, a normal animal can learn that a high level of energy restriction is different from not being food restricted. Like they can use that as a cue to predict something's about to happen, like a foot shock or a food pellet's coming. If you lesion the hippocampus, they can't do that. So it's interoceptive agnosia. They seem to be unaware of what this interoceptive signaling means. Even if they're detecting it at the sensory level, it doesn't mean what it's supposed to mean. It doesn't allow them to appropriately guide their behavior based on that signal or symphony you It seems that some people have so much interoceptive awareness and other people do not. And I wonder how that relates to food intake. You know, we've hosted... world-class choreographers on here and athletes and I always think of the people who move for a living as Being really in tune with their body and obviously they are but then there's the rest of the population where we're not really trained to think about how our body [85:00] he feels in the context of daily living. We just kind of like live. Interceptive awareness of hunger versus fullness that can be impaired with with a high-fat, high-sugar diet as well. So that's a process that is plastic and susceptible to what we eat. I'm editorializing here again, but I feel like so much of the challenge in being a or the task rather of being healthy these days, especially in the United States, is trying to figure out like what the fundamental healthy baseline was or is and trying to get to that because clearly. processed foods, but also just The nature of life, like you even said earlier, like three meals a day for you. Some people, it's one meal a day. Like they all can work. And that's great. That's also part of the challenge is people figuring out what works for them. Yeah. And we don't really have like one system that our brain body connection is optimized for. We're built for. And I'm guessing that's because we went through periods of feast and famine as we evolved. We need this system to be dynamic. also physical activity as it relates to our daily lives. So you and I are physically active, but here we are sitting down. Yeah. We sit and talk. Yeah. We sit and talk a lot. Yeah. Stair screens. To me, I chuckle sometimes that a lot of what we're doing for health nowadays is about moving the outdoors inside. So it's like, they're like red light and they're gyms and they're, we bring plants inside and we, you know, hydrate. What's that? Are these real? They are real. We have, we have shown combined. Yeah. They do a really good job taking care of them despite the black wall. So they get their light. There's this idea that like, think about human evolution from where we are now and kind of like it's the front edge leading forward. And it seems, again, that we're really focus nowadays as a culture, as a health culture, and trying to figure out like, what's the bad stuff that we didn't know was bad? And what's the bad stuff that hijacked us that we didn't realize hijacked us, whether it's highly processed food, or whether it's a, a, a, Advanced glycation and products. Sort of form content. And we have always a process of error correction. We sort of stumble forward, and then we kind of get pulled back. Error correction, keep going. I mean, these are the issues that people really wonder about. Like, what should I eat to keep my memory? I guess the question... What shouldn't I eat? What shouldn't I do? Is far easier to answer. But, The omega-3 fatty acids seem to have a pretty decent literature. There's a woman, forgive me, I'm forgetting the name, we'll put it in the show note caption, who is a laboratory up at UC Santa Barbara who's looked at supplementation with omega-3s during pregnancy and brain size and function in human offspring. It seems like the omega-3s, the polyphenols, enough protein. It seems like those are critical. Yeah, there's a few players that are established. You've hit on the main ones. Yeah. What is your read of the omega-3 literature in terms of, like, have you done experiments where you give animals enhanced levels of omega-3? We have not done that. No, in my lab, we're focused more on what's bad, you know, what's not optimal for brain development. And the only interventions that we've done is either in the gut or to just simply switch to a healthy diet. So I'm aware of those studies, but we haven't modeled that in our lab. Tell me about the microbiome studies. Sure. We. Basically had I'm not a microbiologist. I just want to leave with that. My background is psychology. So I got into the microbiome largely by accident and curiosity about 10 years ago. And we found that in this early life excessive sugar model that we developed, were using in rats years ago, the microbiome was completely different. So if you do like a principal cord analysis and you kind of see the overall pattern of the bacterial population, the animals getting the sugar were just extremely different. And that could be for a lot of things. It could be from the sugar or it could be these animals are consuming a lot of their calories from the sugar. So they're getting less fiber and less nutrients that are in the chow. That aside, individual populations, can we correlate the abundance of this population with the animal's memory performance in one of these memory tests that I described earlier? And in one case we had a population pair of bacteria ODS that was elevated in the sugar group. I think maybe twofold enough that it was significant and noticeable, and it was negatively correlated with memory performance. So then we, in a separate study, we did an antibiotic treatment to kind of wipe out the bacterial population a [90:00] not completely eliminate. And then in that state, we enriched this population into the gut. And the animals showed memory impairments, even though they had never consumed sugar. So we were able to kind of replicate. And in many cases, the memory impairments are more severe when we enrich this population, but it was enriched maybe eightfold and more than what you were getting from the sugar. So that's an example where we found a population that seemed to be negatively impacting performance in the preprint paper that I mentioned earlier, where we have this heat treated age and rich diet model We found another population, this one's lacticoccus, it's a lactic acid producing bacteria that was completely eliminated when we heat treated the diet. And in this case, its performance was positively correlated with memory performance. And we were able to rescue the memory impairments by enriching that population. So these are the kinds of things that we can do with memory. with microbiome studies. There's, of course, fecal transplant. We haven't done much of this, but a lot of people have in the field where you just transplant the fecal and secal content from one group of animals to another. And in that case, you can kind of replicate some of the behaviors simply by doing that. But in that case, you're changing everything. It's not just a single bacterial population. So we've looked more at, can we identify a bacteria that seems to be what we're looking at, and then can we replicate or reverse something by putting it in? Very cool. I'm excited to read the preprint and see the paper come to publication, full fruition, because for a long time, when I talked to my colleagues who work on the microbiome, like, okay, which bacteria are beneficial? And they go, diversity. I go, I get it. Which ones are most beneficial? And I realize in this case, you did a rescue, so you had a diet, although you described it beautifully, a diet that leads to some memory impairments. This is the diet associated with these Maillard high heat reactions. You can rescue some or all of the deficit by replacing a single bacteria. That doesn't mean that increasing that bacteria to super physiological levels will increase memory linearly. So this is offsetting damage, what we call rescue or used to be called gain of function, but now people ran with that term in different directions. It's not a popular term. And I've been just kind of obsessed with like, okay, I get it. Like gut microbiome diversity, but which bacteria are the ones that we want? And it's very, very difficult for anyone experts in that field to give me a clean answer. And I think it's because they just don't know. I think, yeah, I think that's it. I don't think there is a clean answer. And part of the reason for that is... In 2012, that's when the approximately when the human microbiome project ended and before that point we didn't really have an idea about the genetic makeup of the bacterial population in the human gut. So if you go pre-2012, this was not really a field of research. In fact, if you did a PubMed hit, so PubMed is the database for biomedical publications. Ten years ago, you might have pulled up 7,000 hits. Today, 250,000. It's just such a new field of biomedical research that we don't have these answers. And yeah, you can find some bacterial populations that, as I just described, a few that seem to be bad in one context or good in a different context. But then it can be completely flipped in a different study with a different treatment. It's just such a complicated thing. And it's such a new field of research that... I don't think you can say with clarity, like, here are the good bacteria and here are the bad bacteria. We're not even close to that. Yeah, the throwaway answer right now is diversity. It reminds me of the 90s. I'm old enough to remember. It was like exercise. It was like, well, what kind of exercise? And people said, well, weight training isn't good because muscles will turn to fat after you stop. So cardiovascular exercise, you say, what form? And now it's very nuanced. of "high intensity interval training, "longer, slower training, resistance." Now we have answers because there's been 20 plus years or 30 plus years of really good studies and people attacking it seriously. I've got a family member who right now is taking a very high dose spectrum of antibiotics because they unfortunately had a sepsis type situation. And they're very sharp in the mind ordinarily and they were saying they're really struggling to think. like really struggling to think. And so they're trying to repopulate their gut bacteria with, uh, you know, I'm a big proponent based on Sonnenberg's work of low sugar fermented foods. So sauerkraut, kimchi, kimchi, [95:00] for, you know, all these incredible foods that we know really support the gut microbiome. And so they're doing that and feeling better. But of course, they're destroying their gut microbiome intentionally every day at the same time. And I said, if you can just get through this period, defeat the infection, you're going to experience such a robust return, but it's a slow system. Like this isn't the kind of thing where you take a pill and you feel better that the gut microbacteria take as my understanding is it can take weeks or months to really build up a quote with one meal. No, it's not. And it's very plastic dynamic system. Like it, with some exceptions, there's, um, Have you heard of C. diff? No. So this is like an intestinal issue where generally from people in a hospital who are taking antibiotics, antibiotics deplete bacteria, and they'll deplete good and bad. bad bacteria. And with C. diff, there's bacteria that normally keep this C. diff in check. And with C. diff, there's a lot of this which leads to sort of violent GI distress and can even lead to death. And there's an FDA-approved fecal transplant procedure for this specific disease. Syndrome so and I believe it's it's Typically with a single transplant amazing is enough to correct this in a high percentage of individuals So there's you know, there's a bright future for this. I don't think we're there yet. I mean to my knowledge that's the only FT approved There could be others but this one I'm aware of fecal transplant or targeted bacterial treatment But I think it's just such a new field of research where we're definitely in the baby stages of understanding this complex relationship. I was a little bit dismayed when I heard early on that you're. ideal gut microbiome is really a step the upper threshold of that is established in the first three years of life and i thought yeah there's no way my parents got this exactly right but then we learned that it's a little bit like the way learning and neuroplasticity was discussed it used to be considered that okay up until your teens early 20s that was the opportunity for wiring the brain a particular way and then it's locked in and we know that's not true at all. And so there's great plasticity, if you will, to the system, which I find immensely reassuring. And diet is a huge, and probiotics, these are... This is how you change that plasticity. I'd like to take a quick break and acknowledge our sponsor, Function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. Function not only provides testing of over 160 biomarkers key to your physical and mental health, improving your health from top doctors. For example, in a recent test with Function, I learned that some of my blood lipids were slightly out of range. As a result, I decided to start supplementing with natokinase, which can naturally help reduce LDL cholesterol. And it did. In a follow-up test, I could confirm that this strategy worked. My blood lipids are now back exactly where I want them. Comprehensive lab testing of the sort that Function offers is just so important for health. I mean, how else are you going to know what's going on under the hood? And while I've used to be time-consuming, complicated, and expensive. In fact, I used to spend thousands of dollars per year trying to get this kind of data, and the data, frankly, were not all that good. But now with Function, it's extremely easy and affordable. A Function membership is only a dollar a day, $365 a year. And if you think about the information it provides and the health challenges it helps you avoid and the proactive things that it can do for you to enhance your and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com slash Huberman. Yeah, I now think about the gut so differently than I did even a couple of years ago based on conversations like this. Like there's the vagal pathways, which… We don't know the timescales they work on, but they can be relatively fast. And then there's the gut microbiome. I think about the gut microbiome. like gut health as and its relationship to general health, including brain health as I need to give my gut, my, Microbacteria the things they need so that they can create the things that my brain and body need so it's just like raw materials short chain fatty acids leading to your transmitter neuromodulator production like serotonin I just need to give them what they need and no this isn't a you know a product endorsement because my observation is that. It comes mainly from these low-sugar fermented foods getting enough fiber and – not stressing too much because stress can also impair the gut microbiome and then getting enough sleep. And so maybe at the end of the day, it really is all about stress. [100:00] Supporting the gut microbiome, I guess, and there are other things too. It seems that important. And I think it's only really sinking in for me just how important it is. And as a child of the born in 75, like the 90s were just terrible for this. It was like low fat. I guess there was some emphasis on fiber. I lived through that period as well. Yeah, it was it was the advent of margarines and processed foods really came in. Oh, yeah. Fortunately, I never never had an Olestra chip. I wasn't interested in the the the leakage. Yeah, that's it. That was enough of a barrier. We'll move to reinforcement in a moment, but you reminded me of the 90s when the fenfen drugs were released, fenfluoramine drugs. These were supposed to be blockbuster drugs, kind of like the GLPs, but they were basically stimulants, right? And then people started having heart attacks. Is that what happened? Simplomimetics. Yeah, there's some cardiovascular outcomes that were unwanted and led to the discontinuation of that. And then the obesity drug market was dormant for many, many years until around 2012. 10 and beyond when we, um, it wasn't just GLP one drugs. It was a few other ones that have kind of fallen out of favor because the GLP one drugs are the most effective, but yeah, there was a period of time and probably largely due to the fen-fen issue where pharmaceutical companies were not interested in developing obesity drugs. But at this point, 40, over 40% of us adults are obese. It's hard to 40% over 40%. That's it. unbelievable so it's it's uh it's not something that can be ignored now in the 90s wasn't 40% yeah might have been 20 then yeah I mean it's hard for people to remember and I'm not being disparaging of anyone uh but just by recollection like in junior high school or high school there were probably a few kids in my class that were you know visibly quite overweight maybe a couple that were a bit overweight but it was rare you just didn't see it yeah and then there would be shows about people who were they used to call it's not a kind term but they would call it morbidly obese you know and they'd remove them from a building with a crane or something it'll be like geraldo would do an episode and so you were aware that it happened but it was really like these extremes of pathology um you just didn't really see very very lots of very very overweight people back then type 2 diabetes was called adult onset diabetes and for reasons you're Getting at it's now... Not called that because we get, you know, not high percentage, but a noticeable percentage of children and certainly teenagers who develop type 2 diabetes. Do you think it was all the highly processed food industry? I don't want to say anything was all. Yeah. But it certainly contributed. Yeah. Yeah. And I didn't, I grew up. with an ad lib, Access to Mountain Dew. Yeah. Yeah, it was just a different time. Yeah, school lunches used to be like a sandwich with maybe a bag of chips and... Or a cookie. Cookie, yeah. Like it was one or the other you had to pick, you know. And soda wasn't really a – you could get soda, but it was more like a treat. My high school, we had an a la carte lunch. So you could buy like a pretzel with nacho cheese dip. You could buy whatever you wanted. It wasn't – there was no standardized – Here's a healthy... meal. So much has changed so fast, but it looks like the error correction is coming in and hopefully not only in the form of GLPs. I mean, one of the reasons I do this podcast is to try and take You know, showcase serious scientists and clinicians who are extolling the virtues of eating well healthily for people of all ages. But all right. I've alluded to it so many times now. It's almost seems like like I'm teasing. But here we are reward reinforcement enticement. Most people are familiar with the word dopamine. They think of it as pleasure. Most people, thanks to Anna Lemke's book, Dopamine Nation, now, and the book, The Molecule of More, which is also excellent, in my opinion, that dopamine is about craving, wanting, motivation, at least as much and probably more than it is about pleasure. That's true, yeah. and memory. What is the role of the reinforcement pathway? What you and I call the mesolimbic reward pathway? This system, which is the most basic description of it would be a midbrain ventral tegmental area to the nucleus accumbens. That's kind of the classic mesostriatal dopamine projection. And... This system is engaged by palatable foods, so like liquid sucrose, a high-fat sucrose combination. But there's a little bit more to it than that. So you can get the system engaged by a bland-tasting healthy food when an animal's food-restricted. Or you can get the system engaged by... [105:00] by water when an animal's water restricted or even a sodium deplete animal will show a dopamine release in this pathway to to sodium consumption so it's it's it's very much dependent upon the the animal state that said palatable foods tend to tickle that pathway more so than what we consider to be more healthy and bland foods and then of course substances of abuse tap into the same system, albeit to a different degree, but it's definitely a common brain currency for things that we enjoy. So when I hear you say that if we are food restricted or we just haven't, we're very hungry, doesn't have to be fasting, that bland foods can activate the dopamine reward pathway, a reinforcement pathway, excuse me. I'm trying to be more careful with my language. I wonder whether eating highly palatable foods or even just sweet foods changes our threshold for what we consider reinforcing and rewarding. I try to eat healthy and I notice that I really love and crave blueberries and I keep mentioning them and other foods but if I eat healthy foods and I like the way they taste I find that I crave those foods and I don tend to crave other foods presumably because I'm sated. I'm not I'm not excessively hungry. But is there a way that we can recalibrate the system? It seems there is. I think so. I mean, the examples you're saying make a lot of sense. And individuals who consume a lot of sugar, who stop consuming it or consume much less, they change their preference. Something that they normally would have enjoyed is now too sweet. So there's a lot of plasticity in terms of what we want to eat, and that's based largely on what we choose to eat. We can change that, as you've described. You probably weren't craving blueberries when you were 12, maybe. I mean, I've always liked fruit, but I liked other stuff too. And it's not like I actively avoid ice creams and things like that. But I feel like it's different with food than it is with other reinforcing substances. Because if somebody who really craves alcohol, who really craves stimulants, is deprived of those and then gets a small amount of it, I don't know that they say, oh, that just I didn like that experience Usually it like they really like that experience But here it seems we can rewire the circuitry toward healthier choices And maybe even to the point where what used to be rewarding is now aversive. And that is how I feel about like the other day I had a sip of a milkshake, expecting it to be like delicious. And I was like, oh, like I felt like it was like, it was so unbelievably sweet. I felt like I needed a palate cleanser afterwards. and but there was a time when i really enjoyed a vanilla milkshake and i bet if i kept drinking that vanilla milkshake i would start to enjoy it yeah so i'm not sure people understand the plasticity of the system so is it about the amount of dopamine is the is the threat like the upper threshold set by the most potent things like speed milkshakes you know and uh banana split And then if you don't eat those, you don't consume those or take those substances, then you can get to that same high threshold with healthy choices? Or is it that the lower threshold just starts at the upper threshold? Yeah, that I don't know. I don't think those careful studies haven't really been done. I mean there ways to measure with PET dopamine a proxy of dopamine binding in the human brain In animals we have really nice tools I mentioned the acetylcholine sensors with fiber photometry We also use dopamine sensors in my lab So we can record dopamine release, again, when the animals are awake and doing things. We haven't looked at the question you're getting at is how plastic is that system. The most extreme example of the plasticity of that system is with like a conditioned taste aversion, right? So if you have an animal who normally they consume sucrose, they will get dopamine release in that pathway, either when exposed to a cue that predicts that sucrose is forthcoming or the actual consumption of the sucrose. But then if you subsequently treat the or train the animal, that that sucrose consumption is associated with malaise. So inject like a compound that makes the animals uncomfortable for a few minutes they attribute that feeling to consuming the sucrose with that kind of training you will eliminate that dopamine response that you see to sucrose so that's just the most extreme example the plasticity of this system humans have tried to use the aversion approach to learning basic giving people things that make them feel sick or electrically shocking them to try and [110:00] Everything from, these are not ethical studies, but people have... in the, in the old days, like the sixties and seventies, they tried to use this to like conversion therapy, right. For, for a sexual orientation, obviously terrible. Um, and fortunately that's illegal, uh, now, but the, but, but, I'm not aware of any really good studies showing that people will quit smoking if they're like electrically shocked when they pick up a cigarette. My understanding of these studies, maybe this is not true, but I was told by somebody who worked in this general area that people basically just figure out how to endure the shock. Like that's how rewarding nicotine is. And I wonder if there's... something going on with the processed food industry Um, I, aspect too because you I don't know that people really enjoy those foods. I feel like there is, when we hear that they're addictive, I don't know that that's the proper word, but they are impairing people's health. But there seems to be this thing where people get into this kind of like, It's not pleasure. It's not a hedonia, but it's this kind of like mind. I don't want to say mindless, but there's there's some no man's land of. eating and consuming, not getting the thing they're looking for, that looks a lot like addiction. That looks like chronic drug use, but it's not like they're getting high off the food. Yeah, I mean, it's tricky making the comparisons because Yeah, there's a common currency in the brain for substance abuse and palatable foods, but... you have to eat every day. You know, like this isn't, it's not a choice. And there's a lot of controversy in whether there can be an addiction to food. And I know I'm going to take... Aside on either... Either side of that one, but if you look at the DSM Criterion for substance abuse or addiction you can make an argument that there is food addiction based on those Criterion, but that doesn't mean that it's the same thing. Yeah, continued use right in itself for others Yeah, inability stopped as I decide desire to these kinds of things late last year There was a really interesting set of videos that were authenticated the discussion was should um food stamps be you allowed to be used to uh purchase soda and someone from the um American Heart Association was asked on this panel, what do you think? Do you think soda is healthy? And they did this incredible... but really dismaying, in my opinion, tap dance around, well, you know, in the context of this and this. I mean, they did everything they could to avoid answering the question, basically. Sugar Lobby is very powerful. Yes, historically. Are these health associations like the American Heart Association, are they really like in bed with the sugar lobby? To me, that seems a little bit like a like a movie that I'm hoping isn't real. But. In the end, I think they took soda off the list of things that could be purchased with these stamps. I believe that's the outcome because there was enough social pressure because of social media and this just went wild. But is it really the case that our medical industry is in bed with the processed food industry? I mean, hospitals have some of the worst food in the world. Not Stanford Hospital, but I'm sure not USC. Definitely not USC. And that's understandable why they feel they need to do that. But you just go, my God, the nutrition here is just dreadful. And this is a hospital. So my mind goes to like, it might be true, but is it true? Do we know? It certainly seems possible. I mean, I've As someone who's researched the negative impacts of sugar consumption, I've had a few brushes myself with the sugar lobby. Oh, really? In my career. Have you had someone... at tailing your car not quite to that level okay all right more of a public facing statements but um But yeah, to the extent that that's... influencing our policy I don't know. So you've had the sugar industry giving you shit, basically. Yeah, early in my career we had a... It wasn't even published yet. It was from our early life sugar model that I talked about earlier where there was a press release. It wasn't through... Me trying to get it noticed, it just got picked up for something. And when you get press, that's when... The Sugar Lobby... for lack of a better term, may have a forward public statement about that particular study. To try and protect themselves. Yeah, exactly. And generally it's not a That's a great study kind of comment. That was a long time ago. Yeah. Don't worry. You're safe. Actually, by saying this here, you're actually safer now. Also, the world's changed. Nobody trusts big institutions anymore, especially medical-related institutions, which in many ways – is both good and bad. Right. Because if you were a-- Definitely could be. God forbid someone has to do [115:00] surgery, you want an excellent surgeon, like you can't just like, you can't just like health and wellness that, you know, but, but the, and on and on. But it's, I do think we've experienced a tide change. You know, I think the United States is really on board that things need to change. In fact, this week, we have an episode out with Michael Pollan, who's written extensively about the food industry and plants and health. And, and he actually was very, it was really remarkable. anyone wants to see it. He really said, he's like, in order to move the health of this country forward, it needs to be a bipartisan effort. Like the fact that there's an emphasis on improving nutrition, but it really just focused on food dyes. And he wasn't so thrilled about that. But then he actually tipped his hat to some of the things that the administration has been doing, but then also pointed out some of the things that they were doing, like related to liberating the And is able to say we need to get away from the politics if we ever want to move forward and be an actually healthy country. I think we still have a long ways to go. We do. There's hope. There's hope. And you and I are young enough, and our gut microbiomes hopefully are healthy enough that we will remember what we need to know moving forward. Exactly. And there's this whole other generation of young kids that grew up. I'm realizing, like... Thinking about food, nutrition, exercise, sure, through the fire hose of social media where there's a lot of bad information too. But many, many of them think about taking really good care of themselves. And if they grew up in a home where that wasn't a priority, they think about it and they're helping people. And I like to think that things are changing. Before we wrap, I do have a question about oxytocin. Yeah. hormone neuromodulator educate us on the role of oxytocin in the context of food intake and nutrition. It's been known for quite some time that oxytocin can reduce appetite and food intake. And through careful studies from Harvey Grill and others, we have identified the brainstem as being the most robust target of oxytocin signaling to reduce food intake. So oxytocin is released or created in the PVH and the hypothalamus, released into the circulation. the brain and some of those neurons project to directly to the brainstem and that system seems to be an important system for reducing food intake mainly through the level of meal size making meal size smaller increasing satiation we had a study recently where we were looking at its role in the hippocampus and in this case we found some results that were a little bit surprising I should say there's a phenomenon in humans that rodents also show it's called the social facilitation of eating so if you and I are if you're eating alone you might eat less than if you're eating with a group of people and if those people are familiar to you, you're going to eat more than if they were unfamiliar. So that's kind of the gist of the phenomenon. And we can model this in rodents. And we found that that phenomenon requires oxytocin signaling in the hippocampus. So if you genetically turn down the signal, the animals don't show that effect. So this is kind of a different role for oxytocin because under these conditions in this brain region, it's actually promoting intake in a social context. It's really complicated, like most things in the brain are. But historically, it's been a unit direction that oxytocin in the brain reduces food intake. But some of recent findings from our lab and others are saying, well, maybe, yeah, but it might depend on the social context, for example, and where the signal is getting to. Well, Scott, thank you so much for coming and sharing your mechanistic data. I love that you're highly mechanistic. organization of these cholinergic affinits to the hippocampus because I think that's more of an aficionado question. But it's clear that you're studying a really, really important system for people health of all humans, and especially right now with the highly processed food thing, but also the GLPs and also this explosion of discoveries on the microbiome and the positive explosion of people that are interested in doing what they can for their brain and bodily health. You're clearly in the right area, evidenced by the fact that I said if you had a vault of money, what would you study? You're like, what I'm doing right now. So you're clearly in the right you do and it's not lost on me and it shouldn't be lost on the audience that you do that work [120:00] taxpayer dollars. So you're working on our behalf for our health. So, and you're very busy. So thanks for coming here today. Appreciate you. Thank you very much. Appreciate it. It's been fun. Great. Next time, bring your dog. I will. Awesome. Thank you for joining me for today's discussion with Dr. Scott Konosky. 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