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How brain synapses work and fuel themselves with fat.

Episode Summary: Dr. Timothy Ryan talks about the high energy costs of synapses, the role of mitochondria and glycolysis, and challenge the long-held view that the brain relies solely on glucose by discussing new evidence that neurons burn fats from lipid droplets for fuel, especially during activity. The talk touches on metabolic flexibility, links to epilepsy treatments like ketogenic diets, neurodegenerative diseases, and future research on brain energy sources.

About the guest: Timothy Ryan, PhD is a professor of biochemistry at Cornell University. His research focuses on the molecular mechanisms of synaptic transmission, particularly vesicle recycling and the bioenergetics that power neural communication.

Discussion Points:

• Synapses are tiny structures with ~100 vesicles per site (on average), converting electrical signals to chemical ones.
• Brain tissue is energy-hungry due to trillions of synapses (in humans), relying on local mitochondria (present in only ~half of synapses) and glycolysis.
• Vesicles use proton pumps and transporters to concentrate neurotransmitters, requiring ATP to maintain gradients.
• Neurons are metabolically fragile; cutting fuel supply quickly impairs synapses.
• Dogma held brains don't burn fats, but new work shows neurons form lipid droplets (fat stores) that are invisible because constantly used for energy via beta-oxidation.
• Silencing neurons builds lipid droplets like resting muscle; activity speeds their breakdown, indicating demand-driven fat use.
• Inhibiting neuron-specific fat-processing enzymes accumulates droplets and induces torpor (hibernation-like state) in animals, signaling metabolic stress.
• Ketogenic diets aid epilepsy by shifting to ketones; fats may explain this, with potential ties to aging and neurodegeneration like Alzheimer's.
• Brain may be a "hybrid" fuel user (glucose + fats), with open questions on fat sources and roles in cognition or disease protection.

Related episode:

• M&M 158: Ketosis & Ketogenic Diet: Brain & Mental Health, Metabolism, Diet & Exercise, Cancer, Diabetes | Dominic D'Agostino

*Not medical advice.

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Episode Summary: Dr. Eugene Chang talks about the microbiome’s role as a vital organ, the impacts of antibiotics and Western diets on microbial health, and strategies for restoring a damaged microbiome through diet and fecal microbial transplants. They delve into microbiome dysbiosis, its links to modern diseases, and Chang’s research on personalized microbiome interventions.

About the guest: Eugene Chang, MD is a physician-scientist and Professor of Medicine at the University of Chicago, specializing in gastroenterology. His research focuses on the gut microbiome as a vital organ influencing metabolic and immune health.

Discussion Points:

• The gut microbiome is a vital organ, acquired early in life, that supports metabolic and immune functions, but can be disrupted by antibiotics, leading to diseases like C. difficile colitis.
• Western diets, high in saturated fats and low in fiber, contribute to microbiome dysbiosis, linked to modern conditions like inflammatory bowel diseases, obesity, and allergies.
• Microbiome health is better assessed by functional markers (e.g., short-chain fatty acid production) than taxonomic diversity, as diversity varies widely among healthy individuals.
• A patient with severe food intolerance due to antibiotic-induced microbiome damage was treated over 50 weeks with a tailored diet, restoring healthy microbiome function.
• Different dietary fibers (e.g., beans vs. seaweed) are metabolized at varying rates, affecting gut health; fermented foods like kefir can bypass digestion issues.
• Diet can rapidly reshape the microbiome within 24-48 hours, but severe dysbiosis may require microbial transplants if key microbes are extinct.
• Chang’s research shows a high-fiber, low-fat diet outperforms fecal microbial transplants in restoring microbiome resilience in mice post-antibiotics.
• Future microbiome medicine may involve personalized “omni microbial transplants” targeting both small and large intestines for comprehensive restoration.

Related episode:

• M&M 203: Metagenomics, Microbiome Transmission, Gut Microbiome in Health & Disease | Nicola Segata

*Not medical advice.

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The genetics of sleep duration and sleep timing.

Episode Summary: Dr. Ying-Hui Fu discusses her research on the genetics of sleep, focusing on natural short sleepers who thrive on 4-6 hours of sleep and the heritability of sleep traits like duration and timing. She explores how sleep efficiency, rather than just duration, may explain why some need less sleep without health deficits, and delves into the molecular and circadian mechanisms regulating sleep.

About the guest: Ying-Hui Fu, PhD is a neuroscientist and professor at UCSF, where her lab studies the genetics of human sleep behaviors, particularly sleep duration and schedule.

Discussion Points:

• Sleep Traits Are Genetic: Sleep duration (how long you sleep) and sleep schedule (when you sleep) are partially heritable, with most people needing 7-9 hours, while rare natural short sleepers thrive on 4-6 hours.
• Natural Short Sleepers: These individuals fall asleep quickly, have high sleep efficiency, and live healthy, active lives without deficits, possibly due to faster toxin clearance and repair during sleep.
• Sleep Efficiency Matters: Short sleepers may complete restorative sleep processes (e.g., clearing toxins, repairing damage) more efficiently, allowing them to need less sleep.
• Circadian & Entrainment Pathways: Sleep timing is regulated by a molecular clock and environmental cues like light, with mutations in entrainment pathways causing extreme schedules (e.g., early bedtime or night owl tendencies).
• Modern Lifestyle Harms Sleep: Stimuli like blue light and tense media disrupt sleep patterns, leading to widespread sleep deprivation and health risks.
• Shift Work Risks: Shift workers face higher risks of diseases like cancer and neurodegeneration due to disrupted sleep cycles, though genetic background influences susceptibility.
• Finding Your Sleep Rhythm: A two-week vacation without stimulants or artificial light can help determine your natural sleep schedule and duration.
• Sleep’s Health Impact: Poor sleep is a major factor in aging and diseases like Alzheimer’s, making it as critical as diet and exercise for health.

Related episode:

• M&M 237: Circadian Biology: Genetics, Behavior, Metabolism, Light, Oxygen

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