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Episode Summary: Dr. Michael Wheeler talks about neuroimmune interactions, exploring how the immune system and brain communicate, particularly through the blood-brain barrier and meninges; how chronic stress and inflammation can alter brain circuits, contributing to mood disorders like depression; how drugs like psilocybin and MDMA may reduce inflammation by modulating immune cells in the meninges, offering potential therapeutic benefits.

About the guest: Michael Wheeler, PhD is an Assistant Professor of Neurology at Harvard Medical School. His lab studies how immune responses influence behavior, mood disorders, and addiction.

Key Conversation Points:

• The blood-brain barrier (BBB) is not as impermeable as once thought, allowing immune signals like cytokines to influence brain function even in healthy states.
• Chronic stress can weaken the BBB, increasing inflammation and affecting mood-regulating circuits, potentially contributing to depression.
• Microglia, the brain’s resident immune cells, help maintain neural circuits by pruning synapses and regulating metabolism.
• Psychedelics like psilocybin and MDMA can reduce inflammation by prompting immune cells (monocytes) to leave the meninges, potentially via vascular effects.
• These psychedelics may act in a context-specific “window,” requiring a dysregulated tissue state to exert anti-inflammatory effects, not as broad-spectrum anti-inflammatories.
• Neuroinflammation may underlie some treatment-resistant depression cases, suggesting immunotherapy could complement traditional psychiatric treatments.
• The brain encodes peripheral immune signals, like gut inflammation, in specific circuits, which can “remember” and recreate inflammatory responses.
• Aging may naturally increase blood-brain barrier leakiness, heightening the brain's susceptibility to peripheral inflammation.
• Future research aims to explore how psychedelics influence plasticity and their potential in treating inflammation-related diseases beyond psychiatry.

Related episode:

• M&M 2: Psilocybin, LSD, Ketamine, Inflammation & Novel

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Episode Summary: New research on how dietary fats, particularly omega-6 fatty acids like linoleic acid, influence triple-negative breast cancer progression by activating the mTOR pathway, a key regulator of cell growth; role of the FABP5 protein in enhancing cancer cells’ sensitivity to omega-6 fats; differences between breast cancer subtypes; broader implications of dietary balance for health.

About the guest: John Blenis, PhD is a Professor of Pharmacology at the Meyer Cancer Center at Weill Cornell Medicine. Nikos Koundouros, PhD is a postdoctoral fellow in Blenis’ lab.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Key Points:

• mTOR pathway acts as a cellular “brain,” sensing nutrients like amino acids, glucose, and fats to regulate growth. Its dysregulation can drive cancer.
• High dietary omega-6 fatty acids, like linoleic acid found in seed oils, can fuel triple-negative breast cancer growth by activating mTOR.
• FABP5, a lipid chaperone protein, is overexpressed in triple-negative breast cancer, making these tumors more sensitive to omega-6 fats, suggesting its potential as a therapeutic target.
• Modern diets with high omega-6 to omega-3 ratios disrupt inflammation balance, unlike historical 1:1 ratios, potentially increasing cancer risk.
• Genetic variations and cancer subtypes highlight the need for tailored dietary recommendations, as blanket nutrition advice may not suit all patients.
• While omega-6 fats exacerbate existing triple-negative breast cancer, their role in initiating cancer remains unclear, requiring further study.
• High omega-6 intake may influence other cancers (e.g., prostate, colon) and chronic diseases like obesity, linked to FABP5 and inflammation.

Related episode:

• M&M 200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Gane

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Episode Summary: Dr. Gyorgy Buzsaki discusses the hippocampus’s role beyond memory and spatial navigation, delving into its broader functions in cognition, action planning, and brain-body interactions; how hippocampal rhythms, like sharp wave ripples, influence memory consolidation, glucose regulation, and metabolic health, challenging conventional neuroscience assumptions; the interplay of brain rhythms, sleep, and preconfigured neural dynamics; the history and conceptual foundations of neuroscience; and more.

About the guest: Gyorgy Buzsaki, MD, PhD is a professor at NYU. He leads a lab investigating how neural circuits underpin cognition, particularly through oscillations and brain-body interactions. His work has significantly advanced understanding of memory formation and spatial navigation.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Key Conversation Points:

• Hippocampus isn’t just for memory or navigation; it may orchestrate action planning and abstract representations of the world, shaped by evolutionary constraints.
• Brain rhythms, like sharp wave ripples, synchronize neural activity, enabling efficient communication and impacting bodily functions like glucose homeostasis.
• Sharp wave ripples, prominent during non-REM sleep and consummatory states, are critical for memory consolidation and may link sleep disruptions to metabolic disorders.
• Buzsaki challenges the idea of memory as fixed synaptic patterns, proposing it’s more like dynamic, cloud-like sequences, endlessly reconfigurable.
• The brain’s intrinsic dynamics prioritize action generation and learning from consequences over external representations.

Related episode:

• M&M 16: Sleep, Dreams, Memory & the Brain | Bob Stickgold

*Not medical advice.

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• KetoCitra—Ketone body BHB + potassium, calcium & magnesium, formulated with kidney health in mind. Use code MIND20 for 20% off any subscription (cancel anytime)
• Lumen device to optimize your metabolism for weight loss or athletic performance. Use code MIND for 10% off
• Readwise: Organize and share what you read. 60 days FREE through link
• Athletic Greens: Comprehensive & convenient daily nutrition. Free 1-year supply of vitamin D with purchase.
• MASA Chips—delicious tortilla chips made from organic corn and grass-fed beef tallow. No seed oils or artificial ingredients. Use code MIND for 20% off

For all the ways you can support my efforts