Brain Ponderings podcast with Mark Mattson

The ends of chromosomes are called telomeres. In dividing cells a reverse transcriptase called telomerase adds a six-base DNA repeat to the telomeres thereby preventing their shortening. Telomere shortening occurs in proliferative tissues during aging and has been associated with a range of diseases. This led to the dogma that the only function of telomerase is to lengthen telomeres. In this episode Professor Gabriele Saretzki and I talk about our discoveries of non-telomeric functions of the telomerase protein in neurons including effects on gene expression mitochondria, and autophagy. We also talk about the potential of drugs that increase telomerase levels for the treatment of neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. LINKS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120688/pdf/NRR-17-2364.pdf https://onlinelibrary-wiley-com.proxy1.library.jhu.edu/doi/epdf/10.1002/jnr.1073 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938226/

Neuroscience professor Gyorgy Buzsaki discusses brain rhythms, neural syntax, and the emergence of cognition from action. He explores the synaptic basis of theta and gamma rhythms, the role of oscillations in brain communication, and the influence of sub-cortical inputs and neuromodulators on memory formation. Buzsaki also delves into the role of serotonin in REM sleep, the evolutionary perspective on brain mechanisms, and the impact of skipping breakfast on productivity and learning.

In this episode I talk with professor Thiruma Arumugam of Latrobe University about research on the effects of intermittent fasting on brain health and vulnerability to disorders such as stroke, Alzheimer’s and Parkinson’s diseases. This research was prompted by evidence that daily caloric restriction with time-restricted feeding, and every other day food deprivation can extend lifespan in rats and mice. Subsequent studies showed that intermittent fasting can protect neurons against dysfunction and damage in animal models of epilepsy, stroke, Parkinson’s disease and Alzheimer’s disease. Clinical trials then demonstrated that intermittent fasting can suppress inflammation and improve glucose regulation. Collectively, this research led to the popularization of intermittent fasting as way of improving general and cognitive health. Professor Arumugam talks about his research on intermittent fasting effects in stroke and vascular dementia models, and his ‘omics’ studies of the effects of intermittent fasting on brain neurochemistry, and the possibility that some beneficial effects of intermittent fasting can be transmitted from parents to offspring via epigenetic mechanisms. LINKS: Professor Arumugam’s webpage: https://scholars.latrobe.edu.au/tarumugam Book: https://www.amazon.com/Intermittent-Fasting-Revolution-Optimizing-Performance/dp/0262046407  Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039826/pdf/nihms979409.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913738/pdf/nihms958771.pdf Intermittent fasting and brain transcriptomics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9617005/pdf/11357_2022_Article_537.pdf  

Accumulation of toxic proteins in neurons that wither and die is a fundamental problem in neurodegenerative disorders - Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia, ALS, and Huntington’s disease. In this episode Professor David Rubinsztein at the University of Cambridge talks about how impaired autophagy results in the accumulation of the toxic proteins.  Aging, and genetic and environmental factors may impair autophagy and thereby result in neurodegenerative disease. Neuroscientists and neurologists are developing ways to stimulate autophagy and thereby prevent the accumulation of toxic proteins. LINKS: Professor Rubinsztein’s lab page:  https://www.cimr.cam.ac.uk/staff/professor-david-rubinsztein-fmedsci-frs Review on autophagy in neurodegenerative disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930707/pdf/nihms-1771452.pdf Article on removing toxic proteins in neurodegenerative disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456907/pdf/nihms-1007879.pdf Impaired autophagy and amyloid accumulation in Alzheimer’s disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174056/pdf/41593_2022_Article_1084.pdf

The facts that all human behaviors are controlled by the brain and that all crimes involve behaviors beg the question of if and how advances in neuroscience might improve the criminal justice system. Professor Stephen Morse at the University of Pennsylvania Law School and Center for Neuroscience and Society on problems of individual responsibility and agency. He is a pioneer on research at the interface of the law and neuroscience. In this episode Morse provides an historical perspective on NeuroLaw with examples of specific cases in which brain imaging data have been used as evidence as to a defendant’s mental state and responsibility. We also talk about psychopathy and drug addiction as predisposing factors in criminal behaviors and responsibility. Having been immersed in NeuroLaw for many decades, Morse concludes that substantive contributions of neuroscience to the law are very limited, but that this may change with future developments in the science.   LINKS: Professor Morse at Penn Law: https://www.law.upenn.edu/faculty/smorse/ Law and Neuroscience: report of the President’s Bioethics Commission: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033539/pdf/lsu012.pdf  NeuroLaw: Challenges and Limits: https://pdf.sciencedirectassets.com/276230/1-s2.0-C20190004591/1-s2.0-B9780128213759000037/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBwaCXVzLWVhc3QtMSJHMEUCIQDs%2F4PvoOovmb4J3nRy%2BIWJJm53ySCmeZ1m98ssPst45QIgf68T%2BYxRptjPz7G9wOXSA%2BgsesoxqkneG7dp4pZVtA8qswUIRRAFGgwwNTkwMDM1NDY4NjUiDGYAnlyiJhDC0fbDyiqQBUvl9RpbUHDEK7euZ3es2RO64UC3nA5dgPifofNG%2FA%2BxoTNlLLZo51v7RcON%2BWsZ0u7iASLCW08cEEABDRqOTrEpKYsbrf6PoMBXd9wYQbxs43YFjfZZa4VbkT594rQd9iR2%2B%2F4LHLRXi0hQVn4k2fGyQ%2Banl9L03kitshZpykjS8XAcEVPYRKWCZg6Jzpq6IMc2yAJ2kdNjKQbi%2BeBFSCVU3RQFkrBdpG7Bo1gFZfF8rL%2FLUwl0%2B2hb9N8jgzNzzni3WN7e3ughQcEh82%2Bg%2FaYT1FT83YIaYpnOjNIV%2BjgcKJWZ82D841CDSANw%2BPjLV6x7uZUqD9C2zhebrq0K4q8y4ylDGzamDM%2BqXgMHvp1vrB8%2FIWr4y17HN26XYw59MAXBNgCzbv0S45KRxvj%2FzTFTmf7h9RZbDfUVxJHoB3YtL4KsRzcuhT8UCsDcRW%2FosHx%2Bku8zfW3%2F4PvGsKbxWx%2BL7N1unXsjNZO8a5bCM4ABOMiJJMu6%2FYPfuqQ1TJn7hZLlHOqfmGineCO8UfSL%2BTu6n3gltTjBNJH0uOWZVi4Op6cU1Mmz223kWufye49wTyvWM8vHnvpidlL3h6Wrq1cxeycWFtBqHhrPrFbuOuykZdH12LEVCzTr6rDwVwPe8ZXQE%2Fp1t8hq6DqBBTqC%2BPfIUdlwRCKbeh6d0HGZJzvvVkd6AzfoZ8UkNZh1iBFvdmpPwSfRln6cIFD7RKnDTYaR8%2B8B5VxG0br75rKSYdn54zVE8PwtuPvq1uiseUcIwmJ%2BXhj2qZSXFP664Gi5dFsAK8MDUZD80TSKuj7EGvkXs9VbaL05OhDVnG9cl31JyNejWwKCKG%2BeFBPuIBD8kEHwGqxeFpojNqx1nlu8d1IvMPDX3qkGOrEB6XtS6d8NeOPl5NkCEZAOurR09k3ffY0%2BIjvh8lXHuXbrRL8mKfvFCxgR%2F81i%2F6c4VwWzRgloQVEOnjcwMpFtCkPCztkuqPcEfwas0Jl7Bwc3VapJTITwmXu2DY3rF6zHlz5sKWg50bWup7JCODKOc3FUKQD5vfYUk2RpkZP5uHsxbi0OBd7pIeeP2PCWjGbZ7vxB1GnPgy8V%2F0WmKPaeT0rtsef4vCzR5BlWB1yrMhGW&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20231024T125857Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY2UJW5E5N%2F20231024%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=99ad1749a56b56597d9dbad545cd01d5715f58e79851a16c9558d80fe1ade2bf&hash=525472894c4bf63126822c9f34d8803fa325777ca4e8c7082ac033a0d30af25b&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=B9780128213759000037&tid=spdf-04e98b0c-1706-4bb3-b6b4-3a98d2aa235f&sid=aa84f1e132a57745745831c5ff1dcd2ff1c2gxrqa&type=client&tsoh=d3d3LXNjaWVuY2VkaXJlY3QtY29tLnByb3h5MS5saWJyYXJ5LmpodS5lZHU%3D&ua=0f105b50045d58500107&rr=81b264ee3cc08c57&cc=us

Even as the carry out their usual functions molecular components of cells are damaged by oxygen free radicals and other processes. Cells remove such cellular trash by moving it into ‘acid baths’ called lysosomes in a process called autophagy. Research during the past 30 years has revealed the molecular mechanisms of autophagy and have provided evidence that impaired autophagy occurs in neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease.  In this episode professor David Rubinsztein provides an historical perspective on the discovery of autophagy and the current understanding of the molecular regulation of this fascinating process.  LINKS: Professor Rubinsztein’s lab page:  https://www.cimr.cam.ac.uk/staff/professor-david-rubinsztein-fmedsci-frs Review on autophagy: file:///Users/markmattson/Downloads/s41580-020-0241-0.pdf  Review on autophagy in neurodegenerative disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930707/pdf/nihms-1771452.pdf

Expert in hormesis Edward Calabrese discusses the significance of hormesis in biology and medicine. They explore topics such as the beneficial effects of low-level stress, the co-evolution of plants and herbivores, hormesis and longevity, and the forces against healthy habits and prevention. They also touch on the positive effects of exercise on mood and well-being, personal nutrition and supplements, and the exploration of toxins in plants.

Inconspicuously tucked under the cerebral cortex at the back of the brain the cerebellum was long believed to only function as a controller of smooth and accurate body movements. During the past 40 years professor Rich Ivry at the University of California Berkeley has made major contributions to research that has revealed a much more complex repertoire of functions of the human cerebellum including roles in cognition, perception, and language. It turns out that there are at least as many neurons in the cerebellum as there are in the entire rest of the brain and that the cerebellum has strong connections to regions of the cerebral cortex involved in learning and memory and decision-making. In this episode professor Ivry talks about how different experimental approaches and modern technologies have been used to elucidate the functional organization of cerebellar circuits and the consequences of cerebellar dysfunction. LINKS: The Ivry Laboratory at Berkeley:  http://ivrylab.berkeley.edu/rich-ivry.html Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514106/pdf/nihms-1679908.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686189/pdf/nihms-1530513.pdf   Examples of studies of patients with damage to the cerebellum: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200308/pdf/awac072.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245126/pdf/elife-66743.pdf

Chronic pain affects more than 20 percent of people and is the leading cause of disability and loss of productivity. Recent development in technologies and protocols for electrical non-invasive or invasive stimulation or inhibition of specific pathways in the brain or spinal cord are being developed.  At the forefront of this area of neurology is Dirk de Ridder, Professor of Neurosurgery at Otago University and co-founder of the BRAI3N Center for Neuromodulation in Ghent Belgium.   In this episode he describes the triple network model of brain circuitry for pain: a lateral painfulness pathway from the spinal cord to the brain; a medial pathway in the brain that mediates suffering; and an inhibitory pathway for pain suppression.  He talks about how EEG recordings can be used to determine which pathways are altered in patients with chronic pain and therefore which location and protocol for stimulation is most likely to be effective.  Rapid progress in the development of these technologies is resulting in much needed help for those who suffer from and are disabled by chronic pain.   LINKS   BRAI3N Center (Advanced, International, Innovative and interdisciplinary neuromodulation https://www.brai3n.com/en/   Triple Network Model of Chronic Pain https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934778/pdf/fneur-13-757241.pdf   Burst stimulation for chronic pain https://www.brainstimjrnl.com/action/showPdf?pii=S1935-861X%2823%2901872-7   Chronic pain is a brain imbalance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966784/pdf/fcab014.pdf  

The discomforting feeling of hunger evolved to motivate searching for food and is therefore critical for survival. However, for modern-day humans living in environments where food is continuously available excessive hunger can result in obesity. In this episode Yale University professor Tamas Horvath talks about ‘hunger neurons’ in the hypothalamus and how they are regulated by glucose, fatty acids, and signals coming from the gut. He also discusses interesting roles for mitochondria in the hunger neurons in their sensing of metabolic states. His research is also providing important insight into alterations in neural circuits that occur in anorexia nervosa.  Links:  Professor Horvath’s Lab page: https://medicine.yale.edu/lab/horvath/ Review articles: https://www.cell.com/action/showPdf?pii=S1550-4131%2815%2900483-0 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634671/pdf/nihms729589.pdf Anorexia mouse model: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415190/pdf/BioProtoc-13-15-4730.pdf