Brain Ponderings podcast with Dr. Mark Mattson

Most people are familiar with the ultrasound imaging used to visualize in the body such as muscles and tendons, organs, and developing fetuses in the mother's womb. The sound/pressure waves generated by ultrasound are also used in physical therapy and the disruption of kidney stones. In this episode I talk with Professor Jurgen Götz at the University of Queensland about how ultrasound can affect neuronal network activity in the brain and can also be used to enhance the delivery into the brain of large molecules such as antibodies and neurotrophic factors. Much of our discussion revolves around the potential use of ultrasound in Alzheimer's disease. LINKS: Professor Götz' lab page: https://qbi.uq.edu.au/profile/1513/j%C3%BCrgen-goetz Review article on ultrasound: https://www-sciencedirect-com.proxy1.library.jhu.edu/science/article/pii/S0896627323001228 Preclinical studies of ultrasound therapy for memory enhancement and Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221310/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760044/pdf/41380_2021_Article_1129.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405237/

In this episode I preview the book SCULPTOR AND DESTROYER'S coverage of the involvement of glutamate as a 'destroyer' of neuronal circuits and people's lives in epilepsy, stroke, Alzheimer's disease, Parkinson's disease, depression, schizophrenia and other neurological disorders. I also talk about the central roles of the neurotransmitter glutamate in the actions of drugs of abuse, psychedelics, and of drugs used to treat neurological disorders. This episode also describes a chapter that considers how people can influence their glutamatergic systems in ways that optimize brain performance and protect against neurological disorders. Links to SCULPTOR AND DESTROYER: https://mitpress.mit.edu/9780262048187/sculptor-and-destroyer/ https://www.amazon.com/Sculptor-Destroyer-Glutamatethe-Important-Neurotransmitter/dp/0262048183?source=ps-sl-shoppingads-lpcontext&ref_=fplfs&psc=1&smid=ATVPDKIKX0DER

The long anticipated book SCULPTOR AND DESTROYER – Tales of Glutamate – the Brain's Most Important Neurotransmitter written by myself, published by the MIT Press, and distributed by Penguin Random House will soon be released (August, 2023) and available at all major book outlets. The book can be preordered before its release. In this episode I describe the roles of 'sculptor' glutamate in evolution, brain development, learning and memory, and energy allocation and metabolism. In the subsequent episode I preview the book's coverage of the involvement of glutamate as a 'destroyer' of neuronal circuits and people's lives in epilepsy, stroke, Alzheimer's disease, Parkinson's disease, depression, schizophrenia and other neurological disorders. I also talk about the central roles of the neurotransmitter glutamate in the actions of drugs of abuse, and of drugs used to treat neurological disorders. The second episode also includes a chapter that considers how people can influence their glutamatergic systems in ways that optimize brain performance and protect against neurological disorders. Links to SCULPTOR AND DESTROYER: https://mitpress.mit.edu/9780262048187/sculptor-and-destroyer/ https://www.amazon.com/Sculptor-Destroyer-Glutamatethe-Important-Neurotransmitter/dp/0262048183?source=ps-sl-shoppingads-lpcontext&ref_=fplfs&psc=1&smid=ATVPDKIKX0DER

Obesity and diabetes adversely affect learning and memory and increase the risk of dementia. Professor Alexis Stranahan at the Medical College of Georgia has shown that visceral (abdominal) fat adversely affects the function and plasticity of neural circuits in the hippocampus whereas subcutaneous fat has beneficial effects on these circuits. Using mouse models of diet-induced or genetic obesity and transplantation of visceral or subcutaneous fat her laboratory found that obesity causes immune cells that accumulate in visceral fat to produce the pro-inflammatory cytokine IL-1beta. The IL-1beta then acts on microglial cells in the brain in ways that impair cognition. On the other hand subcutaneous fat has beneficial effects on cognition. Exercise can counteract the adverse effects of visceral fat and enhance the beneficial effects of subcutaneous fat. In this episode Professor Stranahan talks about this research and its implications for enhancing brain health.. LINKS: Stranahan Lab webpage: https://www.augusta.edu/mcg/dnrm/faculty/stranahan.php Review article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8958382/pdf/nihms-1783794.pdf Visceral fat and IL1-beta: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921429/pdf/zns2618.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108893/pdf/jci-130-126078.pdf Beige fat and cognition: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324783/pdf/41467_2021_Article_24540.pdf Blood – brain barrier breakdown: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363667/pdf/10.1177_0271678X16642233.pdf

One of the most fascinating stories in the history of science: Cannibals in New Guinea; Mad Cows in England; CJD in humans; dying deer and elk in Colorado; and three Nobel Prizes. Once heretical, it is now well-established that certain infectious brain diseases can be caused not by a virus or bacteria, but by a protein we all have in our brains that goes rogue. The protein – cellular prion protein - transforms into a self-replicating PrPSc that destroy brain cells. In this episode Professor Glenn Telling – Director of the Prion Research Center at Colorado State University – talks about the science of prion disorders in humans and animals with a focus on chronic wasting disease in deer and elk. Because prions in these animals have the potential to mutate into strains that can infect humans there is an urgent need to better understand the mechanisms of prion transformation and both intra- and inter-species transmission. Interestingly, the self-aggregating properties of pathogenic prions are very similar to those of amyloid and Tau proteins in Alzheimer's disease, and alpha-synuclein in Parkinson's disease. These similarities suggest a potential for the development of new therapeutic approaches applicable to all of these diseases. LINKS Professor Telling's Labpage: https://labs.vetmedbiosci.colostate.edu/telling/ Related articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874178/pdf/cshperspectmed-PRD-a024448.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268957/pdf/prion0404_0252.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109225/pdf/41582_2021_Article_488.pdf

Epilepsy affects approximately 70 million people worldwide. The performer Prince had childhood epilepsy, President Franklin Roosevelt had epilepsy which was hidden from the public, and the Olympian Florence Griffiths-Joyner died from an epileptic seizure. While drugs that inhibit sodium channels or activate GABA receptors control seizures for many patients, they are ineffective in one-third of patients. Professor Dimitri Kullmann's laboratory at University College London is at the forefront of the development of designer gene therapies for epilepsy. Here Professor Kullmann discusses clinical aspects of epilepsy, animal models of epilepsy, and the new frontier of personalized molecular genetic therapies. LINKS: Epilepsy review article: file:///Users/markmattson/Downloads/nrdp201824.pdf Review on designer receptor technology for the treatment of epilepsy: https://www.thelancet.com/action/showPdf?pii=S2352-3964%2819%2930298-1 Nature Medicine article: autoregulatory gene therapy for focal epilepsy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152911/pdf/emss-77849.pdf Science article: On-demand cell-autonomous gene therapy for epilepsy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613996/pdf/EMS158742.pdf Intermittent fasting, mitochondria, and ketone therapy for epilepsy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478744/pdf/41467_2019_Article_9897.pdf https://www.jneurosci.org/content/jneuro/40/3/694.full.pdf

When we eat a meal containing carbohydrates a peptide called GLP-1 is released into the blood and acts in several ways to improve glucose regulation. It stimulates insulin release from the pancreas, increases insulin sensitivity, and suppresses appetite. A peptide called exenatide originally discovered in the venom of the Gila monster activates GLP-1 receptors and is now prescribed as a treatment for diabetes and obesity. Preclinical studies at the NIH showed that exenatide prevents neuronal damage and improves functional outcome in experimental models of Parkinson's and Alzheimer's diseases. Professor Tom Foltynie at University College London then led clinical trials of exenatide in Parkinson's disease which demonstrated beneficial effects of exenatide. In this episode I talk with Professor Foltynie about GLP1 receptor agonists and how they protect neurons against damage and dysfunction in Parkinson's and other neurological disorders. LINKS Professor Foltynie's webpage: https://www.ucl.ac.uk/ion/research/our-departments/clinical-and-movement-neurosciences/people/prof-t-foltynie Lancet article: RCT of Exenatide in Parkinson's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831666/pdf/nihms939356.pdf Review articles on GLP1 and its effects on diabetes and obesity https://www.cell.com/action/showPdf?pii=S1550-4131%2818%2930179-7 Review article on energy metabolism and Parkinson's disease: https://content.iospress.com/download/journal-of-parkinsons-disease/jpd130335?id=journal-of-parkinsons-disease%2Fjpd130335 Preclinical studies of Exenatide for: Parkinson's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633544/pdf/zpq1285.pdf Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948479/ Huntington's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628604/pdf/318.pdf

Psychologist Richard Petty has been investigating the determinants of people's attitudes, and the situational and individual difference factors responsible for changes in beliefs, attitudes and behaviors. In this episode I talk with Professor Petty about the factors contributing to the recent spike in anti-science attitudes with a focus on identity politics and internet information bubbles. We also discuss how confidence in science can be increased. LINKS: Professor Petty's wepage: https://richardepetty.com/home/ PNAS article "Why are people antiscience, and what can we do about it?" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335320/pdf/pnas.202120755.pdf Article: "The neuroscience of persuasion": https://www.tandfonline.com/doi/epdf/10.1080/17470919.2016.1273851?needAccess=true&role=button

The neural cells in the retina of the eye capture and processes two-dimensional images of our world and send impulses via the optic nerve to the visual cortex where perception of the images occurs. Jeremy Nathans of Johns Hopkins University identified the genes encoding the light-sensitive proteins (opsins) in rod and cone photoreceptors and the molecular basis of color vision. He has made major contributions to understanding how the retina normally develops and functions, and he has elucidated the causes of several diseases of the eye including macular degeneration, retinitis pigmentosa, and Norrie disease. Here he talks about retinal phototransduction, evolution of the eye, and 'Wnt' and 'Frizzled' proteins that control the growth of blood vessels in the retina. Professor Nathan's research is revealing new approaches for therapies for genetic and age-related diseases of the eye. LINKS: Professor Nathan webpage: https://neuroscience.jhu.edu/research/faculty/61 Evolution and physiology of human color vision: https://www.cell.com/action/showPdf?pii=S0896-6273%2800%2980845-4 Frizzled in development and disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103317/pdf/nihms826696.pdf Signaling pathways in neurovascular development: https://www-annualreviews-org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev-neuro-111020-102127 Gene therapy for diseases of the retina: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983345/pdf/jci-128-120429.pdf

Among the more than 8 million species of animals one kills upwards of 600,000 people every year, most of which are children. By transferring an infectious agent into a human's blood female Anopheles gambiae mosquitos cause malaria. Here Chris Potter at Johns Hopkins University talks about his research that is revealing how the nervous system of mosquitos senses the presence of a human and decides whether or not to bite. His research is advancing understanding of the cellular and molecular organization and function of the mosquito brain, and is contributing to the development of new effective and safe insect repellents. He also talks about the promise and potential unintended consequences of genetic engineering technologies, such as gene drives, aimed at eliminating mosquito populations. LINKS Professor Potter's Labpage: https://potterlab.johnshopkins.edu/ Review article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256107/pdf/bjab021.pdf Olfactory centers in the mosquito brain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063964/pdf/ncomms13010.pdf Insect repellents: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832857/pdf/nihms-1539869.pdf Gene drives: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344398/pdf/41576_2021_Article_386.pdf Impact of climate change on mosquito-borne disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334478/pdf/40121_2022_Article_647.pdf