Brain Ponderings podcast with Mark Mattson

Michael Kreutz is Head of the Neuroplasticity Research Group at the Leibniz Institute for Neurobiology in Magdeburg Germany. Using powerful high resolution microscopy and molecular biology tools his laboratory has shown that autophagy occurs within synapses. Synaptic autophagy is stimulated by neural network activity and is critical for their maintenance and for learning and memory. Moreover, evidence suggests that conventional autophagy and exocytic autophagy prevent the abnormal accumulation of pathogenic proteins (Tau, TDP43, etc.) in neurodegenerative disorders. Pharmacological and lifestyle interventions that bolster synaptic autophagy may promote brain health and disease resistance.  LINKS Kreutz Laboratory: https://www.kreutzlab.com/ Review article on autophagy and synaptic plasticity https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900045-5 Activity-dependent protein expulsion in dendrites https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2901009-4 Golgi satellites in dendrites, NCAM, and LTP https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2900703-9  

Belief in supernatural agents and other religious myths arose as a means of ‘explaining’ the unknown and as a tool for social cohesion and hierarchical control of civilizations. Their religiosity is major feature of a ‘believers’ self identity as well as their group identity. Compelling evidence from multiple types of studies have revealed the neurobiological foundations of beliefs in imaginary deities, an afterlife, and other religious myths. In this episode neuropsychologist Jordan Grafman talks about his research and related research showing that neural circuits in the prefrontal cortex convey religious beliefs much as they convey other beliefs (political, economic, etc.). Particularly fascinating are the results of brain imaging studies of mental imagery (e.g., ‘communicating’ with God), religious fundamentalism, and studies of Vietnam veterans who suffered penetrating brain injuries that dramatically affected their religiosity. These studies confirm and extend previous brain imaging studies by showing that spirituality maps to a brain circuit in the periaqueductal grey similar to lesions that cause delusions.  LINKS Review articles https://pmc.ncbi.nlm.nih.gov/articles/PMC9583670/pdf/fnbeh-16-977600.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11638176/pdf/fnhum-18-1495565.pdf  Functional brain imaging and religious experiences https://pmc.ncbi.nlm.nih.gov/articles/PMC2660736/pdf/zpq4876.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3929007/pdf/brain.2013.0172.pdf Brain lesions and religiosity https://pmc.ncbi.nlm.nih.gov/articles/PMC6197485/pdf/nihms958660.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8714871/pdf/nihms-1735983.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11388357/pdf/pnas.202322399.pdf  

Neurological disorders involve aberrant neural network activity. New technologies are needed for establishing at a fine spatial and temporal resolution the nature of the altered network activity – and for restoring activity to or towards a healthy state. Professor Sri Sarma is an electrical engineer and neuroscientist who is at the forefront of this research field. Her research combines learning theory and control systems with neuroscience to develop novel approaches for understanding normal brain function and then developing brain – computer – electrophysiology feedback control systems to improve performance in health and disease.  Her research and technology development is advancing personalized treatments for epilepsy, Parkinson’s disease, chronic pain, and depression.     LINKS  Seizure onset zone neural fragility in epilepsy https://pmc.ncbi.nlm.nih.gov/articles/PMC8547387/pdf/nihms-1743906.pdf Combining interictal intracranial EEG and fMRI to compute a dynamic resting-state index for surgical outcome validation https://pmc.ncbi.nlm.nih.gov/articles/PMC11811083/pdf/fnetp-04-1491967.pdf]  Steering Toward Normative Wide-Dynamic-Range Neuron Activity in Nerve-Injured Rats With Closed-Loop Peripheral Nerve Stimulation. https://pmc.ncbi.nlm.nih.gov/articles/PMC10081946/pdf/nihms-1855381.pdf Internal states during movements https://pmc.ncbi.nlm.nih.gov/articles/PMC10687170/pdf/41467_2023_Article_43257.pdf Sensory – motor feedback control (athletic performance) https://pmc.ncbi.nlm.nih.gov/articles/PMC10998569/pdf/pnas.202319313.pdf Gambling and decision making https://pmc.ncbi.nlm.nih.gov/articles/PMC11352602/pdf/brainsci-14-00773.pdf  

Compelling evidence shows that consumption of high fructose corn syrup in soft drinks and ultraprocessed foods has contributed to the increases in obesity, diabetes, fatty liver disease, and dementia that has occurred during the past 50 years. Professor Richard Johnson’s research has been at the forefront of establishing how fructose adversely affects cellular energetics and function, and what happens to various organ systems with chronic consumption of fructose. Interestingly, cells can convert to glucose to fructose under certain conditions suggesting a roles for endogenously produced fructose in adverse effects of high glucose intake on health. Animal studies have shown that high fructose intake impairs cognition, synaptic plasticity, and neurogenesis. Fructose is also stimulates hunger and food-seeking behaviors resulting in overeating. Evidence further suggests that high fructose during pregnancy can cause abnormal fetal brain development and increase the risk for developmental brain disorders – most notably autism.  LINKS Reviews Fructose and obesity https://pmc.ncbi.nlm.nih.gov/articles/PMC10363705/pdf/rstb.2022.0230.pdf Fructose and uric acid https://pmc.ncbi.nlm.nih.gov/articles/PMC3781481/pdf/3307.pdf Fructose and neuroplasticity https://pmc.ncbi.nlm.nih.gov/articles/PMC12037248/pdf/JNME2025-5571686.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC2694409/pdf/nihms72749.pdf Fructose and autism https://pmc.ncbi.nlm.nih.gov/articles/PMC6779523/pdf/nihms-1537205.pdf  

Major progress has recently been made in understanding the aging process at the molecular, cellular, and organ system levels. This knowledge is now being applied in preventative and interventional health care. Moreover, because of the severe burden of age-related diseases on societies governments are increasingly developing strategies to extend health span throughout their populations. In this episode Professor Brian Kennedy at the National University of Singapore provides a broad perspective on the field of aging research and its translation into actionable countermeasures. He talks about emerging research on ‘metabolic aging clocks’ and their applications to personalized  anti-aging strategies. His experiences in Singapore are particularly enlightening.  LINKS Professor Kennedy’s NUS profile: https://medicine.nus.edu.sg/bch/faculty/brian-kennedy/ Related articles: https://www.sciencedirect.com/science/article/pii/S1568163724004355?via%3Dihub https://www-sciencedirect-com.proxy1.library.jhu.edu/science/article/pii/S1550413124004534 https://pmc.ncbi.nlm.nih.gov/articles/PMC11330810/pdf/fnagi-16-1428244.pdf https://pubmed.ncbi.nlm.nih.gov/40250404/

Remarkable progress has been made towards understanding of the molecular control of neurotransmitter release from presynaptic axon terminals and the responses of the postsynaptic neuron by neurotransmitters. We know that synaptic activity is required for learning and memory but the structural basis of a memory (an engram) remains unknown. Anton Maximov has made major contributions to understanding the molecular control of synaptic plasticity associated with learning and memory.  Here he talks about his research career journey which began in St. Petersburg Russia followed by postdoc training in Dallas Texas and then to the Scripps Research Institute where he is currently a professor and chair of the Neuroscience Department. He and his team and collaborators recently published an elegant technologically-demanding study in Science in which nanoscale resolution ultrastructural analyses was combined with molecular tagging of neurons encoding a memory revealing an increase in synaptic complexity with intriguing presynaptic structural remodeling.  LINKS Anton Maximov Lab page: https://www.maximovlab.org/ Science article https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.ado8316 Structural diversity of chemical synapses: https://www.cell.com/action/showPdf?pii=S2211-1247%2821%2900267-9 Experience dependent neuron remodeling https://www.cell.com/action/showPdf?pii=S0896-6273%2814%2900800-9

The outer membrane of cells is comprised of a lipid bilayer consisting of phospholipids, cholesterol, arachidonic acid, omega-3 fatty acids, and others. Embedded in the membrane are various proteins that play roles critical to the survival and function of the cell. Examples of membrane proteins of particular importance for neurons are: ion channels and ion ‘pumps which control neuron excitability; glucose and ketone transporters which are critical for energy metabolism, and receptors for a myriad of neurotransmitters, neurotrophic factors, and other inter-cellular signaling molecules. In this episode chemistry Professor Allan Butterfield talks about research showing a pivotal role for free radicals generated by the Alzheimer’s amyloid-peptide in triggering a chain reaction attack on membrane arachidonic acid resulting in the release of a toxic lipid fragment called 4-hydroxynonenal (HNE). HNE can bind irreversibly to certain amino acids on proteins (lysine, cysteine, histidine) thereby compromising the normal function of the protein. The Butterfield lab and my lab showed that binding of HNE to ion pump proteins, glucose transporters, and glutamate transporters renders neurons vulnerable to excitotoxicity in Alzheimer’s disease. Interventions that suppress membrane lipid peroxidation or detoxify HNE may prevent or ameliorate Alzheimer’s disease and other neurodegenerative disorders. LINKS Professor Butterfield’s webpage: https://chem.as.uky.edu/users/dabcns Review articles https://journals.physiology.org/doi/full/10.1152/physrev.00030.2022 https://pmc.ncbi.nlm.nih.gov/articles/PMC7502429/pdf/nihms-1583713.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7085980/pdf/nihms-1566301.pdf

A fascinating feature of interactions between two people is that neural network activity patterns in their brain can become synchronized. In this episode Francesco Papaleo talks about research studies in which activities of neuronal networks are recorded simultaneously in interacting humans or mice.  His work has recently focused on the role of interbrain synchronization in the prefrontal cortex in emotion recognition and empathy. He summarizes this research and its implications as follows:   Interacting brains operate as an integrated system, with neural dynamics coevolving over time. Neuronal synchronization across brains has been observed in a range of species, including humans, monkeys, bats, and mice. This inter-neural synchrony (INS) has been proposed as a potential mechanism facilitating social interaction by enabling the functional integration of multiple brains.. Individual responses, such as emotion processing or decision-making, are adjusted and updated based on information that is continuously exchanged among the interacting partners LINKS Dr. Papaleo’s webpage at the Italian Institute of Technology https://www.iit.it/people-details/-/people/francesco-papaleo Review article on multi-brain dynamics https://www.sciencedirect.com/science/article/pii/S0149763424004342?via%3Dihub Self-experience of another’s stress https://www.nature.com/articles/s41593-024-01816-y Cortical – cortical transfer during social interactions https://www.nature.com/articles/s41593-024-01647-x Prosocial vs selfish behaviors https://www.nature.com/articles/s41593-022-01179-2

Neural networks in the brain are active 24/7 and so require a continuous supply of nutrients via the cerebral blood vessels. As we age the cerebral vascular system can become compromised resulting in damage to neurons and a consequent impairment of cognition. Cerebrovascular dementia is a major cause of morbidity and mortality in the elderly but can also occur in younger people as a consequence of genetic mutations. In this episode professor Thiruma Arumugam of LaTrobe University talk about the causes and consequences of cerebral small vessel disease. The good news is that there are several different measures people can take to reduce their risk for cerebrovascular dementia.  LINKS Vascular dementia reviews https://www.sciencedirect.com/science/article/pii/S1568163724000965?via%3Dihub https://pmc.ncbi.nlm.nih.gov/articles/PMC6420146/pdf/emss-81050.pdf Biomarkers of vascular dementia https://www.sciencedirect.com/science/article/pii/S1568163724000655?via%3Dihub Intermittent fasting and vascular dementia https://pmc.ncbi.nlm.nih.gov/articles/PMC11224924/pdf/jomes-33-2-92.pdf

William Brady deploys behavioral experiments, big data analytics, and natural language processing to elucidate how human psychology interacts with social media technology to affect morality, emotions, and decision-making.  Until very recently in their evolution any one human interacted with no more than a few dozen others during their lifetime. Moreover, those interactions were face-to-face. By its very nature social media is often subjecting our brains to situations for which they are not evolved to deal with properly. Politicians, large corporations, and ‘influencers’ with agendas are taking advantage of several features of social media to benefit themselves and their in-group (political party, religion, ethnicity, and more) at the expense of large swaths of society.  Content intended to trigger outrage is a particularly prominent tool in their social media toolbox. In this episode Dr. Brady talks about his research on the spread of moralized content (moral contagion) on social media and how it muffles critical thinking and thoughtful conversations and cooperation amongst individuals with different perspectives on issues. This is big problem for which solutions are not easy given that algorithms are purposely designed in ways that amplify moralized content because this increases the profits and power of those who peddle the outrage, fear, and outgroup hostility and schadenfreude.LINKS Brady lab page: https://williamjbrady.com/  Relevant published articles: https://pubmed.ncbi.nlm.nih.gov/?term=brady+wj+social+media&sort=date&size=200