Brain Ponderings podcast with Mark Mattson

In stressful situations the brain communicates with the adrenal glands stimulating them to release adrenaline and cortisol. This stress responsive neuroendocrine system plays important adaptive roles by regulating energy metabolism, attention, and learning and memory. However, without a recovery period chronic uncontrolled stress such as psychosocial stress can damage neural circuits in the brain and contribute to a range of mental disorders as well as Alzheimer’s disease.  In this episode I have the pleasure of talking with two pioneers in the field of stress research – Professors Marian Joëls and Ron de Kloet. Their work which spans five decades has shown how two different cortisol receptors determine how the brain responds to physiological and pathological stress. They have revealed how a “cortisol switch” determines brain vulnerability or resilience.  Links Marian Joëls’ webpage: https://www.rug.nl/staff/m.joels/cv Ron de Kloet publications on Google Scholar: https://scholar.google.com/citations?user=Eao7yZIAAAAJ&hl=en&oi=ao The “Cortisol Switch” file:///Users/markmattson/Downloads/s41380-022-01934-8.pdf https://www.sciencedirect.com/science/article/pii/S0091302218300116?via%3Dihub  

Clearly demonstrated as being effective for cardiovascular disease, lifestyle medicine is becoming an important discipline for the prevention and treatment of age-related brain disorders including Alzheimer’s and Parkinson’s diseases.  In this episode I talk with Dr. Josh Helman about his experience working with patients at lifestyle medicine centers. He provides his views on what people can do now to reduce their risk for these brain disorders, and what the future holds in terms of therapeutic interventions. LINKS Dr. Helman’s webpage: https://drjosh.com/ Lifestyle medicine approach:  https://pmc.ncbi.nlm.nih.gov/articles/PMC10907160/pdf/main.pdf  

The calcium ion controls neuronal network activity, synapse function and synaptic plasticity, and is a fundamental mediator of learning and memory. With aging and much more so in Alzheimer’s disease the ability of neurons to properly regulate their intracellular calcium levels becomes compromised. Evidence from human and laboratory animal studies have provided compelling evidence that excessive elevation of calcium levels in neurons results in their dysfunction and degeneration in Alzheimer’s disease, as well as in Parkinson’s disease, and stroke.  In this episode, I talk with Professor Beth Stutzmann about her research which has advanced an understanding about how calcium regulation becomes disrupted in neurons in Alzheimer’s disease. Her findings point to excessive release of calcium from intracellular pools (in the endoplasmic reticulum) as being particularly important in Alzheimer’s. This research points to new therapeutic interventions for this devastating disease. LINKS Stutzmann laboratory: https://www.rosalindfranklin.edu/academics/faculty/grace-e-stutzmann/ Relevant articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC7763805/pdf/cells-09-02655.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9894236/pdf/pnas.202211999.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC12305934/pdf/40478_2025_Article_2023.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3091392/pdf/nihms288394.pdf

Long believed to function only as the cell’s powerhouse research is revealing that mitochondria actively control a cell’s response to various types of stress. Even more amazingly mitochondria send stress-related signals between cells. In this episode UC Berkeley Professor Andy Dillin has made major advances in understanding basic mechanisms of aging, how cells and animals respond to stress, and how the aging process can be influenced by mitochondrial responses to stress. In this episode I talk with Andy about his work and its implications for optimizing health and longevity.  LINKS Dillin Laboratory: https://mcb.berkeley.edu/labs/dillin/ Publications https://pmc.ncbi.nlm.nih.gov/articles/PMC10399134/pdf/load001.pdf https://pubmed.ncbi.nlm.nih.gov/32449292/ https://www.cell.com/action/showPdf?pii=S1097-2765%2817%2930395-7 https://pmc.ncbi.nlm.nih.gov/articles/PMC10575585/pdf/sciadv.adi1411.pdf  

While neurons and the circuits the form have been the major focus of brain research the human brain contains at least as many cells that are not neurons of which astrocytes are by far the most abundant. During the past decade there have been numerous studies that reveal novel and very active roles for astrocytes in regulating the growth of neurons, the formation and modification of synapses, the activities of neural networks, and behaviors in laboratory animals. In this episode Marc Freeman talks about the fascinating world of astrocytes including their diversity, complex morphologies, and roles in neuroplasticity and disease processes.  LINKS: Marc Freeman’s webpage at the Vollum Institute: https://www.ohsu.edu/vollum-institute/marc-freeman-phd  Articles discussed in this podcast: https://pmc.ncbi.nlm.nih.gov/articles/PMC11513168/pdf/nihms-2030570.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7897322/pdf/nihms-1657553.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5161596/pdf/nihms-822004.pdf https://pubmed.ncbi.nlm.nih.gov/39386551/

Because neurons in the brain are electrically excitable and active 24/7 the brain consumes relatively large amounts of energy and must adapt to varying demands on its neural networks. The cellular and molecular complexity of the brain presents a major challenge for understanding not only its second-by-second function but also how neural networks are affected by aging and disease. In this episode Dr. Polina Schichkova talks about how large datasets on cellular energy metabolism gene expression are being used to elucidate how aging affects the brain as a whole. Her findings from analyses of data from brains of young adults and elder humans show that aging results in reduced flexibility of the brain’s bioenergetics and electrical activity. Computer modeling reveals how the brain is altered during aging as well as potential interventions to counteract age-related processes.  LINKS Breakdown and repair of metabolism in the aging brain: file:///Users/markmattson/Downloads/fsci-3-1441297%20(2).pdf Multiscale electro-metabolic model of the brain: https://pmc.ncbi.nlm.nih.gov/articles/PMC12112163/pdf/pcbi.1013070.pdf Online modeling: https://www.openbraininstitute.org/jupyterhub_metabolism/user/mpaulmattson@gmail.com/lab/tree/obi_platform_analysis_notebooks/Metabolism/analysis_notebook.ipynb

Research on substance use disorders has largely focused on understanding the key neural circuits and neurotransmitter systems that are altered, and on behavioral and pharmacological interventions. However, emerging research findings suggest that alcohol use disorder (AUD) is associated with alterations in energy metabolism and can accelerate brain aging. In this episode I talk with Dr. Corinde Wiers about substance use disorders with a focus on her recent clinical trials which show that ketone (b-hydroxybutyrate) supplementation can reduce craving for alcohol in people with AUD and can reduce alcohol withdrawal symptoms. We discuss the potential mechanisms that may explain the efficacy of ketone supplementation – and interventions that elevate endogenous ketone production (fasting, exercise, and ketogenic diets) – in AUD.  Whether or not ketogenic interventions are beneficial for individuals with other addictions (opioids, cocaine, nicotine, gambling..) remains to be determined.  LINKS: Dr. Wiers webpage at the University of Pennsylvania:  https://www.med.upenn.edu/apps/faculty/index.php/g332/p9389303 Dr. Wiers’ publications discussed in this podcast: https://pmc.ncbi.nlm.nih.gov/articles/PMC8034849/pdf/abf6780.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8670944/pdf/fpsyt-12-781668.pdf  https://pmc.ncbi.nlm.nih.gov/articles/PMC10901540/pdf/pyae009.pdf  https://pmc.ncbi.nlm.nih.gov/articles/PMC10895037/pdf/fnut-11-1254341.pdf

Appetite (hunger and satiety) is controlled by neural circuits in the brain – particularly in the hypothalamus – and their reciprocal connections to peripheral organs involved in energy metabolism (gut and liver). Understanding the structural organization of these circuits (their synaptic connections) and their neurochemistry (particularly which neurotransmitters are used at which synapses) is of fundamental importance for human health and developing new treatments for metabolic disorders such as obesity and diabetes. Neuroscientist Henning Fenselau at the Max Planck Institute and University of Cologne Germany has made several major discoveries about how food intake and energy metabolism are regulated and the consequences of abnormalities in the underlying neural circuits. Among his recent findings concern how GLP-1 in the gut communicates with the brain via the vagus nerve, and the roles of specific synaptic signals (NPY, opioids, TRH, and GABA).   LINKS Fenselau laboratory page: https://www.sf.mpg.de/research/fenselau   GLP-1, the vagus nerve, hunger, and sugar metabolism: https://www.cell.com/action/showPdf?pii=S1550-4131%2821%2900219-9 Synaptic amplifier of hunger: https://pmc.ncbi.nlm.nih.gov/articles/PMC10160008/pdf/nihms-1882224.pdf Opioids and sugar appetite https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.adp1510 Brainstem – amygdala circuit during fasting https://pmc.ncbi.nlm.nih.gov/articles/PMC11211344/pdf/41467_2024_Article_49766.pdf

One of the most remarkable feats of biological ‘wizardry’ in the animal kingdom is the ability of some cephalopods (octopuses, squids, and cuttlefish) to rapidly change the color, patterning, and texture of their skin so as to blend in with their background. They accomplish these feats through the linking of neural circuits in the visual system and brain to muscle cells that control the dispersion of pigment in specialized skin cells called chromatophores. But the details of the neural circuitry and the computational processes that control the camouflaging process remain largely unknown. In this episode Columbia University neuroscientist Tessa Montague talks about her research on the neurobiology of camouflage and the many challenges that must be overcome to better understand this remarkable phenomenon.  LINKS Dr. Montague’s cuttlefish lab webpage: Tessamontague.com Links to camouflaging cephalopods https://www.youtube.com/watch?v=XocHDvHlcJM https://www.youtube.com/watch?v=Ojb1pxcSr5E Articles on the neurobiology of camouflage https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2901182-X https://www.sciencedirect.com/science/article/pii/S0959438824000382?via%3Dihub https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2900757-1

During vigorous exercise lactic acid (lactate) levels increase in the blood and during fasting and extended exercise the levels of the ketone BHB (b-hydroxybutyrate) increase. In this episode I talk with Stanford University professor Jonathan Long about his recent discovery that lactate and BHB in the blood are bound to the amino acid phenylalanine and that they (Lac-Phe and BHB-Phe) have beneficial effects on metabolic and brain health. Lac-Phe levels increase markedly in response to exercise in mice, humans, and race horses. Peripheral administration of Lac-Phe in suppresses food intake and reverses diet-induced obesity and insulin resistance in mice.  Genetic ablation of Lac-Phe biosynthesis causes hyperphagy and obesity even in exercising mice showing a critical role for Lac-Phe in the beneficial effects of exercise. BHB-Phe has similar effects on food intake and metabolic health. We talk about the potential benefits of Lac-Phe and BHB-Phe for brain health and resilience.  LINKS The Long laboratory webpage:  https://longlabstanford.org/ Lac-Phe articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC9767481/pdf/nihms-1852727.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10635077/pdf/nihpp-2023.11.02.565321v1.pdf BHB-Phe article:  https://www.cell.com/action/showPdf?pii=S0092-8674%2824%2901214-5