Brain Ponderings podcast with Mark Mattson

In this third podcast in the Bioenergetics and Brain Health series I talk about how intermittent exercise and fasting affect brain function, neuroplasticity, and resilience. Research has shown that both of these bioenergetic challenges can enhance learning and memory, improve mood, counteract aging, and protect neurons against injury and disease. I provide an overview of evidence that over periods of weeks and months cycling between challenge (exercise and fasting) and recovery (resting, eating, sleeping) periods stimulates the formation of new synaptic connections between neurons, increases neurogenesis, and bolsters neuronal stress resistance.  These adaptations of brain cells to bioenergetic challenges are mediated by hormonal factors released from peripheral organs including ketones, and by changes in gene expression in brain cells. A better understanding of how bioenergetic challenges affect the brain provides a rationale for incorporating exercise and fasting into lifestyles and is also revealing new approaches for pharmacological interventions in neurological disorders.

Dive into the fascinating world of mitochondria and their crucial role in brain function! Discover how these energy powerhouses are distributed within neurons, and learn about their processes of division, fusion, and disposal. The podcast highlights the significant impact of physical exercise and intermittent fasting on mitochondrial health and resilience against neurodegenerative diseases. Additionally, explore the interplay of neurotransmitters and calcium dynamics, and how metabolic switching enhances brain energy through ketones.

More than 40 percent of the human genome consists of retrotransposons which are DNA sequences related to retroviruses that can jump within the genome and have the ability to replicate although most are dormant.  In this episode Professor Josh Dubnau at the University of Stony Brook talks about endogenous retroviruses and retrotransposons and recent evidence that some of them are activated in neurons during brain aging and may play roles in the pathogenesis of ALS, frontotemporal dementia, and Alzheimer’s disease. Using the powerful molecular genetic tools in Drosophila models the Dubnau and his team have shown that activated retrotransposons can cause pathological aggregation of the protein TDP43 in neurons and the spreading of the TDP43 pathology between cells similar to that which occurs in ALS and frontotemporal dementia. This basic research advances an understanding of brain aging and neurodegenerative disorders and suggests new approaches for preventing and treating these disorders. LINKS Dr. Dubnau’s web page https://renaissance.stonybrookmedicine.edu/anesthesiology/research/Dubnau Review article on endogenous retroviruses and retrotransposons and their putative roles in neurodegenerative disorders https://pubmed.ncbi.nlm.nih.gov/38663088/ Original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC9944888/pdf/41467_2023_Article_36649.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8096092/pdf/pgen.1009535.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6783360/pdf/nihms-1536529.pdf

This is the fist in a short series of presentations on the interrelationships between energy metabolism, brain function and resilience, and disease processes. Overindulgent sedentary lifestyles are increasingly common with adverse consequences for trajectories of brain health in current and future generations. In this series I review findings from studies of humans and animals that are elucidating the cellular and molecular mechanisms by which energy intake and exercise affect structural and functional neuroplasticity. This topic is considered from a bioenergetic perspective with emphases on brain evolution, developmental neurobiology, adult neuroplasticity and disorders of mood and cognition.

Every day we communicate with and influence others via language, decision-making, and actions. The complexities of human social interactions and language begs the question of how the brain processes the relevant incoming information and then generates responses so rapidly and effortlessly. Neurosurgeon Ziv Williams and his team at Harvard Medical School have made major advances in answering these questions.  By recording the activities of hundreds of individual neurons in the brains of non-human primates in game-theory paradigms of social cooperation and conflict he has identified neurons in the prefrontal cortex that encode social agent identity. Moreover, by recording from neurons in the brains of human patients undergoing brain surgery his team has identified neurons involved in single elements of speech production or in the semantic encoding during language comprehension.  These findings not only advance an understanding of the neurobiological underpinnings of social interactions and language, but also provide insight into disorders involving alterations in these processes.   LINKS Dr. Williams Harvard webpage https://zivwilliams.mgh.harvard.edu/ Neuronal circuits for social decision-making https://pmc.ncbi.nlm.nih.gov/articles/PMC8517320/pdf/fnins-15-720294.pdf Social agent identity cells in the prefrontal cortex of interacting groups of primates. https://pmc.ncbi.nlm.nih.gov/articles/PMC8571805/pdf/nihms-1752328.pdf Single-neuronal predictions of others' beliefs in humans. https://pmc.ncbi.nlm.nih.gov/articles/PMC7990696/pdf/nihms-1654341.pdf  Single-neuronal elements of speech production in humans. https://pmc.ncbi.nlm.nih.gov/articles/PMC10866697/pdf/41586_2023_Article_6982.pdf Semantic encoding during language comprehension at single-cell resolution. https://pmc.ncbi.nlm.nih.gov/articles/PMC11254762/pdf/41586_2024_Article_7643.pdf

One in seven people experience migraine headaches while others suffer with even more debilitating cluster headaches. The causes of these headaches are not fully understood and current treatments provide only partial relief.  In this episode pharmacologist Antoinette van den Brink and neurologist Rolf Fronczek describe the clinical features of these headaches, the current understanding of their causes, and hormonal and environmental factors that can trigger the headaches. Drugs that inhibit the peptide CGRP and electrical stimulation of the occipital nerve are among treatments shown to be effective in reducing headache intensity or duration. LINKS University webpages: https://www.erasmusmc.nl/en/research/researchers/maassen-van-den-brink-antoinette https://hoofdpijnonderzoek.nl/en/team/dr-rolf-fronczek/ Migraine headache articles https://journals.sagepub.com/doi/epub/10.1177/03331024241238153 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863119/pdf/10194_2024_Article_1724.pdf Cluster headache articles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018790/pdf/40263_2019_Article_696.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10755111/pdf/main.pdf

Consciousness is one’s awareness of electrochemically conveyed information coming into the brain from the environment via sensory pathways or generated within the brain’s neuronal networks (i.e., thoughts). In popular culture ‘consciousness’ is often portrayed as a mysterious concept or process. However, research that examines the effects of anesthetics, sleep, brain injuries, and psychedelics on neuronal network activity using fMRI, EEG and other technologies is revealing the circuits and activity patterns that enable consciousness. In this episode University of Cambridge Professor Andrea Luppi talks about his research on the neurochemical and neural network level underpinnings of consciousness. His integration of fMRI and brain connectome data suggest the importance of ‘gateway neuronal networks’ and ‘broadcasters’ (executive control networks) in human consciousness.  We also discuss consciousness from philosophical and evolutionary perspectives. LINKS Professor Luppi’s profile at the University of Cambridge https://neuroscience.cam.ac.uk/member/al857/ Recent review article on consciousness https://www.cell.com/action/showPdf?pii=S0166-2236%2824%2900087-0 Gateway regions and broadcasters https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257694/pdf/elife-88173.pdf

In this episode Richard Lu – a professor of pediatrics at the University of Cincinnati Chldren’s Hospital talks about a type of stem cell in the brain called oligodendrocyte progenitor cells (OPC). OPC normally differentiate into the oligodendrocytes that wrap around the axons of neurons providing insulation that greatly speeds up the propagation of electrical impulses. These cells also provide nutrients to neurons and produce proteins that promote the survival of the neurons.  But OPC can and unfortunately do become transformed into cancer cells.  Dr. Lu talks about the normal roles of OPC in brain development and how they can form brain tumors. LINKS: Dr. Lu’s laboratory web page: https://www.cincinnatichildrens.org/research/divisions/e/ex-hem/labs/lu Oligodendrocytes – review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018611/pdf/nihms-1686441.pdf Oligodendrocytes – Brain repair and cancers https://www.sciencedirect.com/science/article/pii/S0969996120303156?via%3Dihub  

Arizona State University Professors Visar Berisha and Julie Liss have combined their expertise in engineering and speech communication to develop and apply novel automated speech analysis technology to the field of neurological disorders. Because of the complexity of human speech and the brain circuits involved speech analysis can provide a window into multiple domains of brain function.  In this episode they talk about their research and how speech analysis can be used as a tool for cross sectional and longitudinal studies of people with or a risk for brain dysfunction. Their published findings range from studies of NFL football players to patients with ALS or a mental disorder. Automated speech analysis may prove useful in the early diagnosis of neurodegenerative disorders and for evaluation of the efficacy of treatments.  LINKS Review article on automated speech analysis and its applications https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074691/pdf/nihms-1062578.pdf Study of NFL players https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939664/pdf/nihms-861058.pdf Early diagnosis of ALS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555482/pdf/41746_2020_Article_335.pdf Assessment of mental health https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10031731/pdf/sbac176.pdf Potential for early diagnosis of Alzheimer’s disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922000/pdf/nihms-1062581.pdf

There are approximately 7000 rare diseases each affecting fewer than 200,000 Americans.  Most rare disorders are caused by gene mutations, manifest in childhood, include neurological problems, and progress rapidly resulting in death in the first several decades of life. Examples include fragile X and Rett syndromes, some childhood epilepsies, Batten diseases, and several types of ataxias,  In most instances there are no treatments that slow or reverse the disease process. In this episode I talk with Professor Erika Augustine who is the Associate Chief Science Officer and Director of the Clinical Trials Unit at the Kennedy – Krieger Institute which is devoted to research on and treatment of neurological conditions caused by genetic disorders, birth complications, or traumatic injuries with a focus on children and adolescents.  Dr. Augustine talks about the scope of the problems faced by patients with a rare disorder, their families, neurologists, government agencies, and the pharmaceutical industry. To exemplify both the challenges and progress towards effective treatments Dr. Augustine focuses on Batten diseases caused by mutations that impair lysosome functions and cause severe progressive neurological deficits that begin early in life. An effective treatment for one of the Batten diseases was recently approved by the FDA providing one of the first successes in moving from basic research to the clinic. LINKS: Dr. Augustine’s biography in Wikipedia: https://en.wikipedia.org/wiki/Erika_F._Augustine Kennedy – Krieger Institute: https://www.kennedykrieger.org/?gad_source=1&gclid=CjwKCAjwl6-3BhBWEiwApN6_ksQGX9fZCTAZpUSzJNw4sHdr2EyRmm_d3tYPHzQpAEOpBuC0uDGZVRoCSGQQAvD_BwE Batten Diseases Clinical Trials: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736171/pdf/nihms-1641434.pdf Enzyme replacement therapy for CLN2 Batten disease: https://www.pedneur.com/action/showPdf?pii=S0887-8994%2820%2930149-1 Gene therapy for rare neurological disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527017/pdf/fnmol-14-695937.pdf