This is a free preview of a paid episode. To hear more, visit mindandmatter.substack.com
Wide release date: July 23, 2025
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.
* Full audio version: [Apple] [Spotify] [Elsewhere]
* Full video version: [YouTube]
* Support M&M if you find value in this content.
* Episode transcript below.
Episode Chapters:
00:00:00 Intro
00:04:57 Synaptic Vesicle Recycling
00:09:19 Proton Pumps & Neurotransmitter Loading
00:15:09 Mitochondria at Synapses
00:20:09 Synaptic Machinery Energy Use
00:26:01 Glucose as Brain Fuel
00:32:56 Lipid Droplets & Fat Storage
00:39:46 Lipid Synthesis in ER
00:45:10 Limitations of Old Experiments
00:52:25 Disease-Linked Lipases
00:57:29 Lipase Inhibition Experiments
01:03:50 Activity-Dependent Fat Metabolism
01:06:02 Inducing Torpor State
01:13:16 Future Directions 01:19:41 Brain Energy & Disease
Full AI-generated transcript below. Beware of typos & mistranslations!