Brain Ponderings podcast with Dr. Mark Mattson

Distributed throughout the brain are oligodendrocyte precursor cells (OPCs) capable of proliferating and differentiating into the oligodendrocytes that wrap around axons (myelination) thereby greatly increasing signal propagation in neural networks. OPCs are essential for axon myelination during brain development, can enhance myelination in response to neural network activity, and can remyelinate axons in response to injury or in diseases such as multiple sclerosis. In this episode I talk with Johns Hopkins Professor Dwight Bergles about his career and work that is identifying the molecular pathways that regulate the proliferation and differentiation of OPCs, their integration into brain circuits and their roles in neuroplasticity in health in disease. During the past quarter century Dwight and his lab members and collaborators made several major discoveries that revealed previously unknown capabilities and functions of OPCs including that they receive synaptic inputs from glutamatergic neurons and respond to neuronal network activity locally and at a distance. And beyond their role in myelination very recent brain-wide cellular and molecular mapping studies suggest an even broader repertoire of OPC functions in the brain throughout life. LINKS Bergles Laboratory: https://bergleslab.com/ Oligodendrocyte Development and Plasticity. https://pmc.ncbi.nlm.nih.gov/articles/PMC4743079/pdf/cshperspect-GLI-a020453.pdf Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. file:///Users/markmattson/Downloads/35012083.pdf Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. https://pmc.ncbi.nlm.nih.gov/articles/PMC3807738/pdf/nihms-463905.pdf Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury. https://www.cell.com/action/showPdf?pii=S0092-8674%2826%2900112-1 Myelin is repaired by constitutive differentiation of oligodendrocyte progenitors. https://pmc.ncbi.nlm.nih.gov/articles/PMC12997438/pdf/nihms-2139155.pdf

How do neural networks in the cerebral cortex transform incoming sensory information to generate perceptions of the world and elicit behavioral responses? This question is being tackled in the laboratory UC Berkeley Professor Hillel Adesnik whose research program is aimed at understanding exactly how microcircuits in the cerebral cortex process sensory information to generate perceptions and drive behavior. To achieve this goal he deploys cutting-edge optical, genetic, and electrophysiological methods to monitor and manipulate specific subsets of cortical neurons in awake behaving mice. In this episode Hillel talks about the organization of neural circuits in the visual cortex and how cortical microcircuits generate and modify sensory precepts. This research is moving the field closer to understanding the neurophysiological mechanisms by which incoming sensory information is integrated with stored information to produce decisions and actions. LINKS Adesnik laboratory at Berkeley https://adesnik.berkeley.edu/ Lateral competition for cortical space by layer-specific horizontal circuits. https://pmc.ncbi.nlm.nih.gov/articles/PMC2908490/pdf/nihms214939.pdf Probing neural codes with two-photon holographic optogenetics. https://pmc.ncbi.nlm.nih.gov/articles/PMC9793863/pdf/nihms-1753572.pdf The logic of recurrent circuits in the primary visual cortex https://pmc.ncbi.nlm.nih.gov/articles/PMC10774145/pdf/41593_2023_Article_1510.pdf Recurrent pattern completion drives the neocortical representation of sensory inference https://pmc.ncbi.nlm.nih.gov/articles/PMC12586158/pdf/41593_2025_Article_2055.pdf Feature-tuned synaptic inputs to somatostatin interneurons drive context-dependent processing https://pmc.ncbi.nlm.nih.gov/articles/PMC12919646/pdf/nihms-2132228.pdf

Lipids (phospholipids, cholesterol, sphingolipids, ceramides, triglycerides, fatty acids, and others) play vital roles as the major building blocks of cell membranes and in energy metabolism, and cell signaling. University of Alberta cell biologist Maria Ioannou is using cutting-edge cell imaging and biochemistry technologies to elucidate how lipids are moved within and between cells, and how those processes are involved in normal brain functions and if and how those processes are altered in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. She discovered that when neurons are subjected to oxidative stress they accumulate oxidized potentially toxic lipids which are then extruded from the neurons in vesicles which are subsequently internalized by adjacent astrocytes thereby preventing damage to the neurons. Apolipoprotein E (ApoE) genotype is a major risk factor for Alzheimer's disease with ApoE4 increasing risk and ApoE2 and ApoE3 decreasing risk. Maria's laboratory provided evidence that the protective ApoEs enhance removal of toxic lipids from neurons wherease ApoE4 exacerbates accumulation of the toxic lipids in neurons Recently her lab provided that excessive accumulation of the lipid glucosylceramide in neurons results in the release of pathological alpha-synuclein in ectosomes which then transfer the alpha-synuclein to adjacent neurons. These finding may help explain how the neurodegenerative process spreads through neural networks in Parkinson's disease. LINKS Ioannou laboratory webpage: https://ioannoulab.com/ Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity https://www.cell.com/action/showPdf?pii=S0092-8674%2819%2930387-3 Protective ApoE variants support neuronal function by effluxing oxidized phospholipids: https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900847-5 Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease: file:///Users/markmattson/Downloads/s41556-026-01871-6%20(1).pdf

Interoception is a term used to describe the processes by which the brain detects, interprets, and responds adaptively to signals (pain, hunger, fatigue, etc.) coming from various organs in the body. In this episode University of Pennsylvania neuroscientist Nick Betley talks about recent research that has revealed key roles for relatively small numbers of neurons in the hypothalamus in interoception. Using cutting-edge imaging and molecular genetic tools Betley and his colleagues have shown how specific hypothalamic neurons can turn off pain signals and suppress inflammation. These findings have important implications for the development of interventions that alleviate chronic pain Intriguingly, they recently discovered that activation of a group of hypothalamic neurons (SF1 neurons) occurs in response exercise and their activation is required for endurance to increase with training. These findings suggest enhancement of hypothalamic SF1 neuron activity might prevent muscle loss during aging or in certain diseases or physical disabilities. LINKS Betley laboratory page: https://web.sas.upenn.edu/betley-lab/ Exercise-induced activation of ventromedial hypothalamic steroidogenic factor-1 neurons mediates improvements in endurance. https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900989-4 Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits. https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2901350-5 A Neural Circuit for the Suppression of Pain by a Competing Need State. https://www.cell.com/action/showPdf?pii=S0092-8674%2818%2930234-4

Normally activity in the brain's neural networks is tightly regulated by the interplay between neuronal excitation by the neurotransmitter glutamate and inhibition by GABA. An epileptic seizure is a dramatic example of what can happen when an abrupt excitatory imbalance occurs. However, excitatory imbalances also occur during aging and contribute to the dysfunction and degeneration of neurons in Alzheimer's disease. In this episode I talk with University of Washington Associate Professor Melissa Barker-Haliski about how neural network activity is normally regulated, the causes of hyperexcitability in neurological disorders, and the benefits and pitfalls of drugs that suppress neural network excitability. LINKS Barker-Haliski lab page: https://sites.uw.edu/mhaliski/ Review articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC11390315/pdf/nihms-2013484.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9096090/pdf/fneur-13-833624.pdf Original research articles: https://www.sciencedirect.com/science/article/pii/S0014488625004510?via%3Dihub https://journals.sagepub.com/doi/epub/10.1177/13872877251343321 https://onlinelibrary.wiley.com/doi/epdf/10.1111/epi.18395?saml_referrer

Stanford Professor Liqun Luo's laboratory investigates the mechanisms by which neural circuits in the brain are assembled during development and how this neuroarchitecture enables their functions throughout life. During the past 30 years his work has provided technical advances that enabled the establishment of roles for specific proteins in the formation of synaptic connections between individual neurons. In this episode I talk with Liqun about experiments using these technologies that revealed specific molecular codes on the surface of neurons that mediate either adhesive or repulsive interactions and thereby instruct synaptic partner matching during development neural circuits. Recent research in his laboratory has shown that the three-dimensional complexity of neural circuits in the olfactory system is achieved by serial reduction to one-dimensional projections. Professor Luo is a member of the National Academy of Sciences and author of "Principles of Neurobiology" a textbook widely used for undergraduate and graduate neuroscience courses. LINKS Luo lab webpage: https://luolab.stanford.edu/ Review article on the architectures of neural circuits: https://pmc.ncbi.nlm.nih.gov/articles/PMC8916593/pdf/nihms-1746805.pdf Article in Science on dimensionality reduction: https://pmc.ncbi.nlm.nih.gov/articles/PMC12614222/pdf/nihms-2120734.pdf Article in Nature on repulsions and synaptic partner matching: https://pmc.ncbi.nlm.nih.gov/articles/PMC12804089/pdf/41586_2025_Article_9768.pdf Article in Nature on altering an olfactory circuit by manipulating cell surface molecular codes: https://pmc.ncbi.nlm.nih.gov/articles/PMC12804075/pdf/41586_2025_Article_9769.pdf

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