Brain Ponderings podcast with Mark Mattson

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

The structure of neuronal networks is remarkably complex and dynamic. Professor Shelley Halpain has been at the forefront of research aimed at understanding how the brain’s “neuroarchitecture” is established during development and changes in response to synaptic activity (neuroplasticity). Here she talks about the ‘cytoskeleton’ of neurons which consists of dynamic protein polymers of actin (microfilaments) and tubulin (microtubules), and how the polymerization state of these cytoskeletal proteins is controlled by the excitatory neurotransmitter glutamate and the calcium ion (Ca2+). Working with her students and collaborators Professor Halpain has elucidated roles for proteins that control actin or tubulin polymerization in the formation and adaptive modification of neuronal circuits. Such structural modifications play fundamental roles in the enduring changes in neuronal circuits involved in learning and memory. Interestingly, one of these proteins (INF2) mediates a process called ‘actinification’ which functions as an adaptive stress response that can prevent the death of neurons in conditions such as stroke and epileptic seizures.   LINKS: Professor Halpain’s Labpage: https://biology.ucsd.edu/research/faculty/shalpain Review article on Neuron Navigators: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877351/pdf/fnmol-15-1099554.pdf Actinification and neuroprotection: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558009/pdf/41467_2022_Article_33268.pdf Navigator control of growth cone internalization of neurotrophin receptors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561856/pdf/mbc-33-ar64.pdf Regulation of actin microfilaments by glutamate: https://www.jneurosci.org/content/jneuro/18/23/9835.full.pdf

Not only are obesity, insulin resistance, and chronic stress bad for peripheral organ systems but they can also wreak havoc on neuronal networks in the brain.  Here Professor Larry Reagan talks about research showing that insulin acts directly on neurons in the brain and thereby plays important roles in synaptic plasticity and learning and memory. Neurons become unresponsive to insulin in obesity and diabetes and this neuronal insulin resistance may contribute to neuronal circuit dysfunction and damage in Alzheimer’s disease. Elevated levels of the adrenal stress hormone cortisol also contributes to the adverse effects of insulin resistance and diabetes on the brain. Regular exercise, healthy dietary and sleep habits, and avoidance of chronic stress can prevent and reverse insulin resistance and excessive production of cortisol.   LINKS: Professor Reagan’s lab page: https://sc.edu/study/colleges_schools/medicine/about_the_school/faculty-staff/reagan_larry.php Review articles on brain insulin and leptin resistance: file:///Users/markmattson/Downloads/nrn4019%20(1).pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642294/pdf/nihms-1756570.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988909/pdf/nihms927597.pdf Original research articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613975/pdf/db150596.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252121/pdf/main.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774048/pdf/nihms285696.pdf

Marten Scheffer is a Dutch mathematician and ecologist who has made major contributions to modeling of complex systems. While he is best known for his work on catastrophic shifts in ecosystems and climate, he has more recently been applying dynamical systems theory to major brain-based problems of individual brains (e.g., belief traps and mental illness) and societies (e.g., inequality and fragility of democracies). Here I talk with Marten about features of dynamical systems – tipping points, basins of attraction, resilience…) and how systems modeling can be used to understand, evaluate, and intervene in detrimental ways of thinking and interacting with others.     Links: Catastrophic shifts in ecosystems: file:///Users/markmattson/Downloads/35098000.pdf Early warning signals: file:///Users/markmattson/Downloads/nature08227%20(1).pdf Belief traps: file:///Users/markmattson/Downloads/pnas.2203149119%20(1).pdf Cognitive distortions: file:///Users/markmattson/Downloads/pnas.2102061118.pdf Shifts in rationality in language: file:///Users/markmattson/Downloads/pnas.2107848118.pdf

Despite many advances in neuroscience the fundamental question of how brains make computations is as yet unanswered.  Progress has been hindered by the inabilities to monitor activities of large numbers of neurons during natural behaviors and to determine the structures and synaptic connections of all neurons involved in circuits mediating computations. Recent progress towards overcoming these hurdles has come from studies of Zebrafish in Professor Rainer Friedrich’s laboratory at the Friedrich Miescher Institute in Basel Switzerland. Here Rainer talks about Zebrafish brain development, structure, and function. and how technological advances in genetics, brain imaging, dense reconstruction of neuronal connectivity, and virtual reality are being used to elucidate fundamental mechanisms by which neuronal circuits make computations.   Links: Rainer Friedrich’s lab page: https://www.fmi.ch/research-groups/groupleader.html?group=119 Virtual reality: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100911/pdf/EMS85577.pdf Review article on Zebrafish behaviors: https://www-annualreviews-org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev-neuro-071714-033857 Odor coding: https://www.cell.com/action/showPdf?pii=S0960-9822%2817%2931452-5 Synaptic balance: https://www.cell.com/action/showPdf?pii=S0896-6273%2818%2930786-4 Dense circuit reconstruction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100684/pdf/sdata2016100.pdf