How Food Choices Shape Memory, Cognition & Cravings | Dr. Scott Kanoski
In a Nutshell
Dr. Scott Kanoski's research shows that high-sugar and junk food diets during development cause persistent hippocampal memory deficits and altered gut microbiome composition that remain even after switching to healthy eating. GLP-1 receptor agonists like Ozempic suppress appetite primarily through vagal nerve signaling from the gut rather than direct brain penetration, while also showing potential benefits for memory and addiction beyond weight loss. Both artificial sweeteners consumed during development and ultra-processed foods impair memory function through microbiome changes and disrupted gut-brain communication pathways involving acetylcholine signaling to the hippocampus.
These notes were generated by AI and may contain inaccuracies.
When Dr. Scott Kanoski began studying how diet impacts neurocognition and memory function, the initial model was a high sugar model. Animals had ad libitum access to a sugar solution with approximately the same percentage of calories as a soft drink that humans consume, while otherwise having healthy food and water. Animals showed hippocampal-dependent memory deficits when older, and these deficits persisted later into life even after they stopped consuming sugar. There may be a role for the microbiome, as there were changes in gut bacteria from the sugar model that may have a functional connection to the memory impairments.
Research has also examined models where animals consumed a total junk food diet, including chocolate peanut butter cups, ruffled potato chips, and rodent high-fat, high-sugar diet. These animals showed memory impairments that lasted even after switching to a healthy diet.
GLP-1 is an incretin hormone secreted from the distal intestines around food ingestion. There is some secretion before the meal starts, additional secretion during the meal, and this enters circulation. There is also a source of GLP-1 produced in the brain in the brain stem nucleus tractus solitarius, where a population of neurons make GLP-1 and extensively send GLP-1 message throughout the brain.
The peripheral GLP-1 and central GLP-1 have very similar effects, both involved in hunger suppression, but they appear to be operating independently with no strong connection between the peripheral GLP-1 physiological system and the neurons that make GLP-1 in the brain.
GLP-1 helps regulate blood glucose levels by stimulating insulin secretion when high levels of glucose are present in the blood. The first application of GLP-1 based drugs was for diabetes treatment, not for obesity. Because they also suppress appetite and food intake leading to body weight loss, they are now more widely known for their weight loss capacity, but started as diabetes treatment.
GLP-1 drugs like Ozempic and Wegovy increase levels of GLP-1 a thousandfold more than naturally experienced levels, making them super physiological. Most known effects are beneficial, with people taking GLP-1 based drugs for over a decade. Clinical trials support efficacy, though side effects include nausea and emesis (vomiting), which can lead to discontinuation. The primary limitation is mitigating these side effects and achieving more long-term efficacy beyond initial weight loss.
Some people are taking far less than prescribed doses, known as microdosing, to offset side effects while still getting appetite suppression and reducing costs. No data exists on microdosing from clinical trials. Placebos are very effective, so some reported benefits could involve placebo effects. Large randomized control clinical trials would be needed before accepting efficacy, and such studies are unlikely given drug companies have no incentive to study lower doses that would reduce sales.
GLP-1 receptors are not exclusively expressed in brain regions controlling appetite and food intake. They are densely expressed throughout the brain, including reward circuitry regions like the mesolimbic pathway, midbrain VTA, striatum, nucleus accumbens, and the hippocampus. This suggests potential applications for GLP-1 receptor agonists in substance abuse disorder treatment and potentially memory disorders and dementia. Preclinical data supports these applications, with clinical data ongoing.
The capacity of GLP-1 drugs to get into the brain relates to applications beyond appetite suppression. First-generation GLP-1 drugs from 2005-2012 had preclinical evidence in rodents suggesting large parts of the mechanism for food intake suppression occurred through brain action. Whether newer generation drugs like Wegovy get into the brain is less clear and controversial.
Fluorescent tagging studies show accumulation in circumventricular organs where there is no blood-brain barrier, suggesting drugs act primarily in these regions. However, fluorescent molecules fade and the brain has autofluorescent signal, so these studies may be missing important information. Better studies using radio labeling with carbon-14 are being conducted by Elizabeth Ria, Bill Banks and colleagues at University of Washington, showing early generation GLP-1 drugs readily get into the brain while newer ones are less clear.
Native GLP-1 likely has a paracrine mechanism of action. The vagus nerve innervates the GI tract with GLP-1 receptors on the terminals. GLP-1 is released from L cells in the intestines and immediately acts on nearby receptors expressed on the vagus nerve. This paracrine mechanism is how both GLP-1 drugs and physiological GLP-1 may produce feelings of satiation.
The vagus nerve communicates within-meal signals that contribute to stopping eating. GLP-1 is a major player in satiation, not exclusively through the vagus nerve but probably largely through this paracrine mode of action. This sends signals to the brain stem, the first site where vagus nerve signals indicate sufficient food intake.
Evidence that the vagus nerve is crucial for GLP-1 action comes from selective lesion studies. When the sensory vagus nerve is lesioned as it comes from the GI tract to the brain, injecting native GLP-1 is not effective in reducing food intake. This work comes from Wolfgang Langhans in Zurich and colleagues. Using short hairpin RNA interference to knock down GLP-1 receptor expression on the vagus nerve also results in animals eating larger meals.
When sweet taste is consumed, there is a cephalic phase response releasing insulin before nutrients get through the GI tract from the simple taste of sugar in the mouth. This prepares the body for blood glucose level perturbations. Preclinical animal models show evidence that disrupting the relationship between sweet taste in the mouth and caloric consequences can cause perturbations in appetite and glucose regulation.
There is no definitive evidence from human clinical trials that artificial sweeteners are good or bad for weight loss. Preclinical animal models show some evidence that habitual exposure to artificial sweeteners disrupts capacity to metabolize sweet taste later and can lead to increased appetite and weight gain.
One study examined animals in the juvenile adolescent stage of development given artificial sweeteners daily within FDA acceptable daily intake levels. Animals consumed it voluntarily rather than through drinking water. When tested as adults, animals showed memory impairments and glucose regulatory changes, including larger insulin spikes when glucose was infused bypassing the mouth. Changes in sweet taste receptor expression on the tongue were also observed.
Three different sweeteners were tested: stevia, Ace-K, and saccharin, with similar effects regardless of which sweetener was used. The study was conducted in rodents consuming artificial sweeteners daily during developmental stages.
The literature on artificial sweeteners remains mixed and inconclusive. There is some evidence that replacing habitual sweetened beverage consumption with artificial sweetened beverages could have beneficial effects on weight loss, but no reliable trend line establishes whether this is definitively good or bad. Without randomized clinical trials to provide definitive answers, individuals must decide whether to be in the experimental or control group based on the current state of evidence, which is somewhat unclear and driven largely by preclinical models.
Memory of eating occasions can have a powerful effect on how much people eat subsequently. In one study by Suzanne Higgs and colleagues, participants consumed a pizza lunch and were later primed to think about the memory of that lunch. When given a cookie taste test a few hours later, those primed to remember their recent lunch consumed fewer cookies compared to groups primed to think about something else or given no priming. The memory of recent eating contributes to eating less at subsequent eating occasions.
Jeff Brunstrom and colleagues conducted a study using tomato soup in a bowl with a peristaltic pump that either added more soup or removed soup without participants' awareness. Participants consumed the entire bowl but the volume they saw differed from what they actually consumed. Immediately after eating, hunger ratings were based on actual consumption rather than perceived volume. However, a couple hours later, hunger ratings were driven more by what participants thought they consumed versus what they actually consumed.
Some people eat significantly more during stress while others experience appetite suppression and forget to eat. The mammalian memory systems evolved in environments where food was not readily available and animals had to compete for resources. The systems traditionally studied for metabolism and appetite control actually promote memory function, which makes evolutionary sense because encountering nutrients was a critical event worth remembering. These satiation systems are tuned into memory systems in the brain, with particular focus on the hippocampus.
There are substantial individual differences in how eating affects cognitive function. Some people feel most focused when they haven't eaten for a while, while others experience sleepiness after eating too much. There is no single optimal pattern for meal timing, frequency, or spacing between eating and cognitive demands. Self-experimentation may be valuable for determining individual responses.
Intermittent fasting represents one effective approach to weight loss, but people can also lose weight by consuming fewer than maintenance calories across three or more meals. George Bray, considered one of the godfathers of obesity research, noted that the best diet is one that people can stick to, and this varies significantly between individuals.
A western diet (approximately 35% calories from fat and 15% from simple sugars) produces hippocampal-dependent memory impairments in animal models within as little as one week, though studies typically run for several months. Hippocampal-dependent memory processes appear more susceptible to negative dietary impacts than other types of memory that don't rely on the hippocampus.
When animals consume a sugar solution during the juvenile-adolescent developmental phase with otherwise healthy food and water available, they show hippocampal-dependent memory deficits later in life that persist even after sugar consumption stops. There may be a role for the microbiome, as sugar consumption produces changes in gut bacteria that could functionally connect to memory impairments.
Animals consuming a total junk food diet (including chocolate peanut butter cups, ruffled potato chips, and rodent high-fat, high-sugar diet) during development show memory impairments that last even after switching to a healthy diet. While these impairments might potentially be reversed through other interventions, the developmental window appears particularly vulnerable to long-term neurocognitive impacts from these foods.
The NOVA classification system categorizes foods into four processing levels but lacks mechanistic specificity about which processing types matter. Heat treating otherwise healthy food at high temperatures for an hour induces the Maillard reaction, which enhances flavor but produces chemical byproducts called advanced glycation endproducts (AGEs). These compounds are normally present in physiology and associated with the RAGE receptor, generally linked to diabetes and aging processes.
Animals consuming an AGE-enriched diet during development show memory impairments as adults. A population of bacteria eliminated through the heat treatment process appears involved, as reintroducing this bacteria reversed the memory impairments.
Memory assessments use a maze approximately table-sized with holes around the edge, where animals use visual spatial cues to remember food locations. Animals crawl into tunnels to eat meals, then researchers test whether they remember tunnel locations the following day. Additional non-food memory tasks involve placing animals in arenas where they must remember which objects they've seen in which locations, with preferential investigation of objects in novel locations indicating memory.
Control animals typically perform above chance levels on memory tasks, indicating they remember food locations or object placements. Animals on certain diet manipulations perform at chance levels, showing no evidence of remembering previous food locations or object placements.
Prospective studies show correlations between midlife dietary patterns and metabolic status (including visceral adiposity) with increased dementia risk later in life. In transgenic Alzheimer's animal models, western diet consumption exacerbates pathology and leads to earlier symptom development compared to healthy diet consumption.
The connections between diet and cognitive outcomes appear more relevant for prevention throughout life rather than switching dietary patterns once symptoms arise. While correlations exist between food intake and Alzheimer's disease, they do not represent direct one-to-one relationships, as some individuals with apparently healthy diets develop the condition.
Exercise can reverse memory deficits caused by western diet consumption in rodent models, with effects occurring partly through direct changes in the brain. Both treadmill and wheel-running exercise models have been used, as water-based memory tasks are avoided due to stress and physical demands that could confound results.
Effective treatments for Alzheimer's remain elusive. Research is exploring connections between the gut and Alzheimer's pathology rather than focusing solely on brain chemical processes. The vagus nerve shows a direct connection to the hippocampus, where lesions impair hippocampal-dependent memory functions.
A Taiwan study from the 1980s examined individuals who underwent trunkal vagotomies for stomach ulcers. This procedure, which cuts the major connection between brain and body, revealed a positive correlation between vagotomy and later dementia development in one small study.
Transgenic Alzheimer's rat models develop amyloid and tau pathology in the hippocampus in an age-dependent fashion. Vagal nerve stimulation devices implanted in these models are sutured to the stomach and deliver electrical stimulation only during eating, triggered by natural stomach expansion and contraction.
These devices have demonstrated the ability to rescue memory impairments caused by unhealthy diets, suggesting potential functional benefits of vagal nerve stimulation in memory impairment models.
Memory systems involving the hippocampus evolved primarily for survival rather than storing pleasant memories. Nothing is more fundamental to survival than maintaining nourishment and hydration. A significant component of hippocampal function involves the gut's ability to communicate with the brain about nutrient timing, amounts, and context.
Beyond the vagus nerve, hormones involved in appetite and metabolism reach the brain through circulating humoral signals. The hippocampus contains receptors for insulin, ghrelin, and leptin, providing insight into the animal's metabolic state. This makes the hippocampus similar to the hypothalamus in receptor expression patterns.
Feeding behavior is not a reflexive response but a complex decision involving foraging choices about when, where, and what to eat. These complex behaviors require higher-order brain inputs beyond basic homeostatic regulatory processes controlled by the brainstem and hypothalamus.
The hypothalamus contains switches for finding food, eating, and stopping eating. A separate body-to-brain vagus-to-hippocampus memory system provides additional input for feeding decisions. When macronutrient ratios are skewed with insufficient micronutrients, essential fatty acids, vitamins, minerals, and protein relative to calories, the memory system suffers.
Human studies by Dick Stevenson and colleagues examined healthy adults' habitual dietary patterns and performance on hippocampal-dependent memory tasks. Connections were found between habitual sugar consumption, saturated fatty acid consumption, and memory test performance. These effects may be reversible through healthier diet consumption.
Human dietary research faces significant limitations due to inaccurate self-reporting, while rodent studies allow 100% accuracy in measuring food intake. Modern phone apps may improve reporting accuracy. Evidence in humans supports rodent findings regarding dietary impacts on memory.
Over 60% of calories consumed in the US come from ultra-processed foods. The technology exists to engineer foods with robust micronutrient content while maintaining palatability. The food industry has successfully created desire for processed foods through marketing, suggesting similar approaches could promote nutritious options.
Standard rodent diets contain 10-15% calories from fat with complex carbohydrate sources, creating healthy baselines that make it difficult to demonstrate beneficial effects of supplementation. This healthy baseline may explain why loss-of-function research has proliferated more than gain-of-function studies.
GLP-1 drugs may create the first widespread thiamine and micronutrient deficiencies in modernized cultures, as people eat less and choose low-nutrient foods. This could result in "skinny fat" populations with muscle loss and micronutrient deficiencies affecting hippocampal function similarly to obesity.
Most people discontinue GLP-1 treatment within two years due to side effects or cost. Clinical trials show no micronutrient deficiency issues, but these trials lasted only 1-2 years and involved controlled diabetic or obese populations.
American comfort foods like fried chicken, pizza, cotton candy, hot dogs, and apple pie contrast with nutrient-dense traditional foods from other cultures. Education on brain-healthy eating is needed, as many seek pills or solutions rather than dietary changes. GLP-1 drugs address weight but not the nutrient component of health.
Any weight loss program should include nutrient and physical activity components, as simply taking medication is not optimal for weight loss. Clinical trials embedded nutritional and physical activity guidelines within their protocols.
The ascending vagal connections from the body to the brain are primarily excitatory, creating arousal rather than calm. Vagal stimulation can restore alertness in patients who are drifting under anesthesia. The gut does not send a unified signal indicating what was eaten. Instead, food produces effects that generate electrical currents sent upward.
The vagus nerve carries distinct signals from different receptors. Mechanoreceptors in the stomach detect distension when food arrives. Chemoreceptors in the intestines detect chemical composition. These signals arrive with different timing as a meal progresses. The neurons of the vagus nerve and nodose ganglia express different receptors and are highly heterogeneous, not all responding to the same stimulus.
Gut-derived information reaches the hippocampus through a three-tier pathway. Signals travel from the brainstem to the medial septum, where acetylcholine-producing neurons project to the hippocampus. Acetylcholine serves as the primary neurotransmitter currency in this gut-brain-hippocampus axis.
Fiber photometry recordings show that acetylcholine release into the hippocampus increases when animals actively eat, hold food, chew, and swallow. When animals pause, acetylcholine levels decrease. The pattern resembles a jigsaw throughout the meal. Importantly, baseline acetylcholine levels are higher at the end of the meal than at the beginning, forming a staircase pattern. The elevated postprandial acetylcholine level enables memory formation about the meal location and context.
The acetylcholine release pattern requires both taste and post-oral nutrient sensing. Animals consuming stevia, a non-nutritive sweetener, do not show the same acetylcholine release patterns in the hippocampus. The combination of taste and nutrient signals appears necessary to drive vagal acetylcholine signaling to the hippocampus.
Interoceptive awareness is a messy and imprecise process compared to visual processing. Humans can discriminate between extreme hunger and extreme fullness but struggle with intermediate states. The hippocampus processes this interoceptive awareness. Patients with dense amnesia due to bilateral medial temporal lobe damage, including the hippocampus, have episodic memory spans of only 10-30 seconds. When these individuals eat multiple consecutive meals, they consume each meal without remembering the previous ones. However, they rate their hunger and satiety levels appropriately on a 0-10 scale, indicating they receive gut feedback but cannot interpret its meaning. The hippocampus is required to understand what interoceptive signals signify.
Interoceptive awareness of hunger versus fullness can be impaired by high-fat, high-sugar diets. This process is plastic and susceptible to dietary influences.
Omega-3 fatty acids, polyphenols, and adequate protein appear critical for brain health. Research from UC Santa Barbara has examined omega-3 supplementation during pregnancy and its effects on brain size and function in human offspring.
Research focuses primarily on identifying harmful dietary effects rather than beneficial interventions. The only interventions tested involve replacing bacterial populations in the gut or switching to a healthy diet.
In early life excessive sugar models using rats, the microbiome composition differs substantially from controls. Principal coordinate analysis reveals distinct bacterial population patterns in sugar-consuming animals. Parabacteroides populations were elevated approximately twofold in the sugar group and negatively correlated with memory performance. Antibiotic treatment followed by enrichment of this population produced memory impairments in animals that had never consumed sugar. In some cases, memory impairments were more severe when Parabacteroides was enriched eightfold beyond sugar-induced levels.
In heat-treated, AGE-enriched diet models, Lactococcus populations were completely eliminated. This population showed positive correlation with memory performance. Enriching this population rescued memory impairments caused by the heat-treated diet.
The human microbiome project concluded around 2012, marking the beginning of systematic genetic characterization of gut bacterial populations. PubMed hits for microbiome research increased from approximately 7,000 a decade ago to 250,000 currently. The field remains too new to identify definitively beneficial or harmful bacteria across contexts. Bacterial population abundance affects hundreds or thousands of other populations, creating complex interactions. The same bacterial population can appear beneficial or harmful depending on study conditions and treatments.
The gut microbiome is a plastic, dynamic system. Recovery from antibiotic depletion requires weeks to months of rebuilding rather than overnight restoration through single interventions.
Andrew Huberman reflects on how his understanding of the gut has evolved, emphasizing the vagal pathways and gut microbiome's relationship to brain health. He describes viewing gut health as providing raw materials to gut bacteria so they can produce needed compounds for the brain and body, including short-chain fatty acids and neurotransmitters like serotonin. Huberman notes that his approach centers on consuming low-sugar fermented foods, getting adequate fiber, managing stress, and prioritizing sleep. As someone born in 1975, he recalls the 1990s emphasis on low-fat diets and the rise of margarine and processed foods.
The conversation shifts to the 1990s Fen-Phen (fenfluramine) drugs, which were stimulants marketed as blockbuster obesity treatments but discontinued due to cardiovascular complications. Following this, pharmaceutical companies largely avoided obesity drug development until around 2010. The current obesity rate stands at over 40% of US adults, compared to approximately 20% in the 1990s. Huberman recalls that in junior high and high school, visible overweight was rare, with extreme obesity cases featured on television shows like Heraldo. Type 2 diabetes was formerly called "adult onset diabetes" but now affects children and teenagers. Both speakers acknowledge that highly processed foods contributed significantly to these changes, with Huberman describing his high school having à la carte lunch options including pretzels with nacho cheese dip rather than standardized healthy meals.
Huberman introduces the topic of reward and reinforcement pathways, noting that most people associate dopamine with pleasure, but it is equally or more associated with craving, wanting, and motivation. Scott Kanoski describes the mesolimbic reward pathway, specifically the ventral tegmental area to nucleus accumbens projection. This system is engaged by palatable foods like liquid sucrose or high-fat sucrose combinations, but also by bland healthy foods when animals are food-restricted, water when water-restricted, or sodium when animals are sodium-depleted. The system's activation depends heavily on the animal's physiological state, though palatable foods tend to engage it more than healthy, bland foods. Substances of abuse tap into the same system.
Huberman asks whether consuming highly palatable or sweet foods changes the threshold for what is considered reinforcing. He shares his personal experience that eating healthy foods leads him to crave blueberries and other healthy options, while reducing cravings for other foods. Kanoski confirms there is significant plasticity in food preferences based on consumption patterns. Individuals who reduce sugar consumption find previously enjoyed sweet foods now taste too sweet. Huberman notes that unlike alcohol or stimulants where deprivation typically increases enjoyment upon re-exposure, food preferences can rewire toward healthier choices, sometimes making previously rewarding foods aversive. He describes recently finding a milkshake unbearably sweet after adopting healthier eating patterns.
Kanoski explains that careful studies on how plastic the dopamine system is regarding food preferences have not been conducted. Human studies can measure dopamine binding via PET scans, while animal studies use dopamine sensors with fiber photometry. The most extreme example of plasticity is conditioned taste aversion, where pairing sucrose consumption with malaise eliminates the normal dopamine response to sucrose. Historical attempts to use aversion approaches in humans, such as electrical shock paired with cigarette smoking, have been largely unsuccessful, with people learning to endure the shock rather than quit the rewarding behavior. Kanoski notes the controversy around whether food can be addictive according to DSM criteria, acknowledging that while food shares brain circuitry with substances of abuse, eating is necessary for survival unlike optional drug use.
Huberman raises concerns about potential conflicts of interest between medical organizations and the processed food industry, noting that hospitals often serve nutritionally poor food. Kanoski acknowledges having encounters with the sugar lobby early in his career when a press release about his early life sugar consumption research prompted defensive public statements. The conversation touches on recent policy debates about whether food stamps should cover soda purchases, with the American Heart Association avoiding direct answers about soda's health impacts. Kanoski notes uncertainty about the extent of industry influence on policy.
Both speakers express that the United States appears to be experiencing a "tide change" regarding food policy, with bipartisan recognition that improvements are needed. Huberman references an upcoming episode with Michael Pollan, who advocates for bipartisan efforts to improve nutrition while noting concerns about the current administration's focus on food dyes and pesticide deregulation. Despite acknowledging significant work remains, both express optimism about changing public attitudes, particularly among younger generations exposed to nutrition information through social media.
Kanoski explains that oxytocin has been known to reduce appetite and food intake, with the brainstem identified as the primary target for these effects. Oxytocin is produced in the paraventricular nucleus of the hypothalamus and projects throughout the brain, including to the brainstem where it reduces meal size and increases satiation. However, recent research from Kanoski's lab reveals a more complex picture. Studies on the "social facilitation of eating" phenomenon—where people eat more in groups, especially with familiar others—show that oxytocin signaling in the hippocampus is required for this effect. When hippocampal oxytocin signaling is reduced, animals no longer demonstrate increased eating in social contexts, suggesting oxytocin can promote intake under certain social conditions rather than universally reducing food intake.
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