Brain Ponderings podcast with Dr. Mark Mattson

The rapid psychedelic effects of the mushroom chemical psilocybin and its long-lasting mood-elevating effects are remarkable. While psilocybin and other psychedelics activate the serotonin 5HT2A receptor the nature of the functional and structural changes responsible for the dramatic effects of psychedelics on perception, mood, and cognition are unknown. In this episode Cornell University Professor Alex Kwan talks about very recent research in his laboratory showing that psilocybin triggers long-lasting changes in the structure of certain neural networks in the brain that may explain the neuropsychological effects of psychedelics. LINKS Kwan lab at Cornell https://alexkwanlab.org/ Review article in Nature Reviews Neuroscience: file:///Users/markmattson/Downloads/s41583-024-00876-0%20(1).pdf Article in Nature: file:///Users/markmattson/Downloads/s41586-025-08813-6%20(2).pdf Article in CELL: https://www.cell.com/action/showPdf?pii=S0092-8674%2825%2901305-4

Here I describe evidence that brain aging can be slowed by lifestyle choices that include exercise, moderation in energy intake, and consumption of plant-based diets. LINKS https://pmc.ncbi.nlm.nih.gov/articles/PMC5913738/pdf/nihms958771.pdf https://www.cell.com/action/showPdf?pii=S1550-4131%2823%2900473-4

In this episode I talk with Case Western Reserve University Professor Andrew Pieper about how it might be possible to restore neuroplasticity and cognition in Alzheimer's disease. The conversation focuses on a recently published study from his laboratory which shows that a chemical called P7C3-A20 that restores energy balance in brain cells can reverse brain pathology and restore cognitive function in a mouse model of Alzheimer's disease. LINKS Pieper laboratory: https://www.harringtondiscovery.org/about/harrington-investigators/andrew-pieper-lab Article discussed in this podcast: https://www.cell.com/action/showPdf?pii=S2666-3791%2825%2900608-1

In this lecture I describe how changes occurring in the brain during normal aging set contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Cellular and molecular hallmarks of aging predispose brain cells to neurodegenerative orders with environmental and genetic factors determining if and when the disease manifests. LINKS: Review articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC3710114/pdf/nihms288391.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7948516/pdf/nihms-1624328.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9242841/pdf/nihms-1685119.pdf

During the past decade several new technological advances have enabled the identification of ensembles of neurons that encode a specific memory trace (engram cells) and for controlling the activity of engram cells so that recall or inhibition of a memory is controlled by the experimenter. The technologies include fluorescence 'tagging' of engram cells and optogenetic activation or inhibition of the engram cells. In this episode professor Tomás Ryan talks about these developments and his own research which provides evidence that memory recall involves competition between different engrams, that forgetting a memory is an active process in which recall of the memory is suppressed. Studies of amnesia have shown that memory engrams can still exist and can be recalled by electrical stimulation. LINKS Review and Perspective articles https://www.cell.com/action/showPdf?pii=S0166-2236%2825%2900153-5 file:///Users/markmattson/Downloads/s41583-021-00548-3%20(1).pdf Engram cell connectivity and memory https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2901512-9 Forgetting and engram expression https://pmc.ncbi.nlm.nih.gov/articles/PMC11537488/pdf/elife-92860.pdf

Recent discoveries show that some neurodegenerative disorders occur because of abnormalities in the processing of RNA in the cell nucleus and/or its export from the nucleus. Johns Hopkins University Associate Professor Shuying Sun is at the forefront of research that is establishing the molecular mechanisms responsible for RNA dysregulation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Her research is contributing to a rapid acceleration of understanding of the causes of ALS and FTD and to the development of new pharmacological and gene therapy-based treatments for these disorders. LINKS Dr. Sun's laboratory webpage: https://sunlab.jhmi.edu/ Review article https://pmc.ncbi.nlm.nih.gov/articles/PMC11790913/pdf/44318_2024_Article_352.pdf Original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC5754368/pdf/41467_2017_Article_2495.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6895427/pdf/nihms-1539444.pdf https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1 https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1 https://www.biorxiv.org/content/10.1101/2025.06.13.659508v1

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This episode begins by highlighting recent evidence showing adverse effects on the brain of excessive activation of the mTOR pathway as a consequence of dietary branched chain amino acid consumption. Then I describe evidence that Beyond the age of 40 years brain aging results in progressive decrements in function which are associated with reductions in gray matter and synapse numbers particularly in brain regions that play critical roles in memory, executive functions, and task switching. Recent progress has been made in identifying molecular markers of brain aging in samples of blood or cerebrospinal fluid heralding a better understanding of factors that accelerate or retard brain aging. This episode reviews some of the salient research in these areas.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This video describes 12 major changes that occur in brain cells during aging and their involvement in decline in brain function and the development of neurodegenerative disorders including dementia and Parkinson's disease.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This is the first of five lectures on the Neurobiology of Aging. The other four lectures cover cellular hallmarks, structural and functional aspects, biomarkers, how neurodegenerative disorders occur during aging, and how aging can be slowed and brain health span extended by lifestyle and dietary changes.

The lipid membrane bilayer of cells is composed of fats including phospholipids, cholesterol, and sphingomyelin. Enzymes called sphingomyelinases can cleave sphingomyelin resulting in the liberation of ceramides which can diffuse within the cell and act as signaling molecules. In this episode I talk with Tulane University Professor Norm Haughey about research in his laboratory and others which have shown that levels of certain ceramides are increased in the brain, cerebrospinal fluid, and blood of patients with Alzheimer's disease, HIV-associated cognitive disorder, and other neurological disorders. Elevated ceramides may provide a biomarker for individuals at risk for these disorders. Dr. Haughey and his collaborators have shown that drugs that inhibit a particular sphingomyelinase can prevent degeneration of neurons and associated cognitive impairment in animal models of Alzheimer's disease and HIV. Norm Haughey's laboratory webpage: https://haugheylab.org/ Relevant articles https://pmc.ncbi.nlm.nih.gov/articles/PMC2907186/pdf/nihms-209661.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC2933928/pdf/nihms200180.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3144420/pdf/nihms309072.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3414665/pdf/znl633.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7852391/pdf/aba5210.pdf https://www.sciencedirect.com/science/article/pii/S0969996123000013?via%3Dihub https://pmc.ncbi.nlm.nih.gov/articles/PMC10334757/pdf/pnas.202219543.pdf