Brain Ponderings podcast with Mark Mattson

Someday it may be possible to restore neuronal networks that have been lost or damaged by brain injury or in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. There are as many astrocytes in the human brain as there are neurons and the astrocytes generally do not die in brain injuries and neurodegenerative disorders. Professor Magdalena Götz has shown that astrocytes can be converted directly into neurons using molecular biology technologies to manipulate a few transcription factors that switch cell fate.  These new neurons grow and form synapses with each other and can integrate into functional neuronal networks and may restore brain function. In this episode Dr. Götz talks about her pioneering work on cell reprogramming that holds great promise for the repair of neuronal networks damaged by trauma, a stroke, and neurodegenerative disorders. LINKS: Professor Götz publications on PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=magdalena+G%C3%B6tz&sort=date&size=200  Professor Götz Wikipedia page:  https://en.wikipedia.org/wiki/Magdalena_G%C3%B6tz Review article in Neuron: https://www.cell.com/action/showPdf?pii=S0896-6273%2821%2900972-7 Selected original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC11239498/pdf/41593_2024_Article_1677.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10719094/pdf/41591_2023_Article_2644.pdf https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2930693-2

The Euclidean geometry that we learned in our primary education concerns man-made shapes such as rectangles, triangles, and perfect circles. However the shapes of molecules, cells, and organ systems (and their dynamic changes over time) are more complex. Some biological structures exhibit fractal geometry which is defined as “shapes and patterns that appear similar at different scales” (recursive iteration). Examples of biological structures exhibiting fractal geometry include the branches and roots of trees, blood vessels, lung airways, and the dendritic arbors of neurons. In this episode I talk with Antonio Di leva a neurosurgeon and neuroscientist at Macquarie University School of Medicine about fractal geometry and its applications to basic and clinical neuroscience. Fractal structures of neural networks optimize the energy efficiency of the brain.  Dr. Di leva talks about emerging applications of fractals to diagnosis and monitoring of neurological disorders, neurosurgery, neuroimaging, and computational intelligence. Fractal analyses are not limited to structures and can also be applied to studies of recursive features dynamic processes including neural network activity.  LINKS Dr. Di leva’s webpage: https://mqneurosurgery.com.au/prof-antonio-di-ieva/ Book ‘The Fractal Geometry of the Brain’: https://link.springer.com/book/10.1007/978-3-031-47606-8  Review articles: https://journals-sagepub-com.proxy1.library.jhu.edu/doi/full/10.1177/1073858413513927 https://journals-sagepub-com.proxy1.library.jhu.edu/doi/full/10.1177/1073858413513928

Polyamines are small organic molecules that are acquired in the diet and can also be synthesized in cells. Spermidine is a polyamine that is increasingly recognized as playing important roles in counteracting aging. Foods with high amounts of spermidine include whole grains, broccoli, and natto (fermented soybeans). Professor Stephan Sigrist at the Free University of Berlin who is widely known for his fundamental contributions to understanding how specific proteins and their interactions control the rapid release and reuptake of neurotransmitters at the presynaptic active zone.  In this episode I talk with Stephan about his recent fascinating discoveries that have revealed important roles for spermidine in synaptic plasticity, and brain health and resilience. Spermidine stimulates autophagy which may be required for the anti-aging effect of dietary energy restriction. He talks about the intriguing molecular mechanism by which spermidine accomplishes these feats. LINKS Sigrist lab page: https://www.bcp.fu-berlin.de/en/biologie/arbeitsgruppen/genetik/ag_sigrist/mitarbeiter/leiter/sigrist/index.html Spermidine counteracts brain aging: https://www.cell.com/action/showPdf?pii=S2211-1247%2821%2900255-2 Autophagy mediates beneficial effects of spermidine on memory during aging: https://www.nature.com/articles/nn.3512.pdf Spermidine preserves synaptic plasticity during aging: https://pmc.ncbi.nlm.nih.gov/articles/PMC5042543/pdf/pbio.1002563.pdf Spermidine, fasting and longevity: https://pmc.ncbi.nlm.nih.gov/articles/PMC11392816/pdf/41556_2024_Article_1468.pdf Clinical trial of spermidine – effects on cognition in older folks: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2792725

In the moment most people can readily distinguish between information that is coming into the brain from their senses and what information their brain is generating. However, when recalling information stored in the brain’s neuronal networks the ability to distinguish between what was real and what was imagined becomes more problematic.  How does the brain keep track of what we actually experienced in the past and what we imagined happened?  In this episode Jon Simons who is Professor of Cognitive Neuroscience at the University of Cambridge talks about his research that is elucidating the neurobiological basis of reality monitoring including which brain regions and neuronal networks are involved, individual differences in people’s reality monitoring ability, the effects of early life experiences and aging, its alterations in schizophrenia and autism, and the broader implications of this research for individuals and societies in the [mis]information age.  LINKS:  Professor Simon’s laboratory web page: https://www.memlab.psychol.cam.ac.uk/  Review article https://www-sciencedirect-com.proxy1.library.jhu.edu/science/article/pii/S1364661317300554  Selected original research articles https://pmc.ncbi.nlm.nih.gov/articles/PMC2292823/pdf/ukmss-1581.pdf https://www.sciencedirect.com/science/article/pii/S0010945216301745?via%3Dihub https://pmc.ncbi.nlm.nih.gov/articles/PMC4860197/pdf/10803_2016_Article_2749.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5292760/pdf/main.pdf

In this episode Emory University and Chinese Academy of Sciences Professor Keqiang Ye talks about his fascinating and ground-breaking trail of discoveries that have revealed previously unknown mechanism responsible for the production and accumulation of damaging fragments of the APP and Tau proteins in Alzheimer’s disease (AD) and the alpha-synuclein protein in Parkinson’s disease (PD). He discovered an enzyme called AEP that cleaves Tau and alpha-synuclein into self-aggregating toxic fragments.  Eliminating or disabling AEP can prevent the disease process and preserve brain function in mouse models of AD and PD.  More recently, in a series of studies his laboratory has provided evidence that the generation of rogue Tau and alpha-synuclein fragments first occurs in neurons surrounding the intestines and then propagates up the vagus nerve to the brain. Moreover, his group has shown that certain species of bacteria in the gut can promote the development of the disease. Finally, Professor Ye has developed drugs that inhibit AEP or activate BDNF receptors as potential treatments for AD and PD.  LINKS Key publications: https://pmc.ncbi.nlm.nih.gov/articles/PMC4224595/pdf/nihms623922.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5315368/pdf/nihms825673.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10482867/pdf/41467_2023_Article_41283.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8408610/pdf/EMBJ-40-e106320.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6951265/pdf/41422_2019_Article_241.pdf Professor Ye’s Google Scholar page: https://scholar.google.com/citations?user=VSP72CMAAAAJ&hl=en

Among high income countries the United States spends the most on health care and yet has the lowest life expectancy. A high percentage of Americans suffer with chronic diseases including obesity, diabetes, cardiovascular disease, mental disorders, and Alzheimer’s or Parkinson’s diseases. There are several reasons why people living in the wealthiest country have poor health all attributable to unrestrained capitalism. In this episode I talk about issues with pharmaceutical industry that contribute to the overall poor quality of health and health care in America with a focus on drugs for neurological disorders.  Drug prices in the US are much higher than in other countries and prices are increasing at a rate more than 5 times the rate of inflation. Pharmaceutical companies spend nearly twice as much on marketing as on research and development and overstate their costs for drug development by ~400 percent. The US is one of only two countries that permit direct advertising of drugs to consumers. Pharmaceutical company representatives lobby doctors and congress.  There are also major issues concerning clinical trials of drugs including conflicts of interest, lack of data transparency, and lack of head-to-head comparisons of a new drug with an existing drug. There are potential solutions to these problems but will require major new government regulations. https://pubmed.ncbi.nlm.nih.gov/31034803/ https://pmc.ncbi.nlm.nih.gov/articles/PMC8649053/pdf/nihms-1751070.pdf

In this episode I talk with Professor Jason Shepherd about his discoveries concerning a fascinating protein called Arc.  In response to synaptic activity Arc levels rapidly increase in postsynaptic dendrites as a result of local translation of the Arc mRNA in the dendrites. Arc plays a critical role in long-term memory although it is not necessary for learning. But perhaps the most interesting twist in the Arc story comes from the Shepherd labs discovery that Arc can self-assemble into highly ordered structures that are essentially identical to the capsids that form the coat of viruses. I talk with Jason about evidence that Arc can bind mRNAs and transfer them from one neuron to another in extracellular vesicles. These findings reveal a whole new mechanism for regulating neuronal network function. Moreover, recently Jason and his lab members have demonstrated a key role for Arc in the trans-neuronal propagation of Tau pathology which is an important advance in understanding how the neurodegenerative process spreads throughout neuronal networks in Alzheimer’s disease and other neurodegenerative disorders – and also has implications for novel approaches for halting the disease process.  LINKS: The Shepherd laboratory page: https://www.shepherdlab.org/ Key publications from the Shepherd lab: https://pmc.ncbi.nlm.nih.gov/articles/PMC8041237/pdf/nihms-1661230.pdf https://www.cell.com/action/showPdf?pii=S0092-8674%2817%2931504-0 https://pmc.ncbi.nlm.nih.gov/articles/PMC11526995/pdf/nihpp-2024.10.22.619703v1.pdf

Among high income countries the United States spends the most on health care and yet has the lowest life expectancy. A high percentage of Americans suffer with chronic diseases including obesity, diabetes, cardiovascular disease, mental disorders, and Alzheimer’s or Parkinson’s diseases. There are several reasons why people living in the wealthiest country have poor health all attributable to unrestrained capitalism.  In this episode I talk about how large-scale monoculture crops used to produce addictive ultraprocessed sugars such as high fructose corn syrup adversely affect health including brain health. The widespread availability of such obesogenic high-calorie ultraprocessed foods at low prices have propelled a transgenerational epidemic of obesity, diabetes and associated chronic brain disorders. Increasingly sedentary lifestyles exacerbate the problem. In also talk about the health benefits of a range of organically grown vegetables and fruits with a focus on a few specific chemicals they produce that act on cells in ways that bolster their function and resilience.    Here are links to a few articles that provide more detail on the problem and potential solutions. https://pmc.ncbi.nlm.nih.gov/articles/PMC9904196/pdf/nihms-1868184.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8748512/pdf/41467_2021_Article_27645.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC6779523/pdf/nihms-1537205.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5841445/pdf/nihms946635.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC4081729/pdf/pr.113.007757.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC4586293/pdf/nihms678801.pdf

Humans have the amazing ability to instantly recognize the faces of hundreds or even thousands of people they have previously met or seen in pictures or movies. Studies of people with brain injuries that render them incapable of recognizing faces and recordings of neuronal activity in people during face recognition have shown that networks in the occipital and temporal lobes adjacent to the visual cortex mediate facial recognition.  Professor Bruno Rossion is at the forefront of research that is revealing the neurophysiological underpinnings of face recognition. By recording and stimulating neurons in the face recognition circuits of numerous research participants Rossion’s laboratory has elucidated how the brain captures and recalls the gestalt of a face without dwelling on specific features of the face. LINKS: Review articles on the neurobiology of face recognition: https://pmc.ncbi.nlm.nih.gov/articles/PMC9954066/pdf/brainsci-13-00354.pdf https://www.sciencedirect.com/science/article/pii/S0028393224000800?via%3Dihub https://www.sciencedirect.com/science/article/pii/S0149763424000034?via%3Dihub  

In this final episode of the Bioenergetics and Brain Health series I talk about changes that occur in brain cells during normal aging, and in Alzheimer’s disease, Parkinson’s disease, and stroke with emphasis on alterations upstream and downstream of cellular energy metabolism. The episode concludes with examples of therapeutic interventions that target those age- and disease-related alterations.  LINKS: Hallmarks of Brain Aging https://pmc.ncbi.nlm.nih.gov/articles/PMC6039826/pdf/nihms979409.pdf Brain Energy Rescue: https://pmc.ncbi.nlm.nih.gov/articles/PMC7948516/pdf/nihms-1624328.pdf The Hormesis Principle of Brain Health and Resilience https://pmc.ncbi.nlm.nih.gov/articles/PMC5209274/pdf/nihms834422.pdf