Brain Ponderings podcast with Dr. Mark Mattson

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

In this episode I provide an overview of the evidence that certain chemicals produced by plants and fungi are beneficial for brain function and health. I focus on the fact that the function of these phytochemicals or mycochemicals in the plants or mushrooms is to defend them from being consumed by insects and other animals. We and other animals evolved mechanisms to tolerate the noxious chemicals. We avoid too much of them because they have a bitter taste, and our cells respond to the chemicals by activating adaptive stress responses (antioxidant enzymes, protein chaperones, neurotrophic factors, etc). By these hormesis-based mechanism way plant-based diets enhance brain resilience and counteract aging and disease processes. LINKS Articles on dietary phytochemicals and brain health https://pmc.ncbi.nlm.nih.gov/articles/PMC4081729/pdf/pr.113.007757.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5841445/pdf/nihms946635.pdf https://www-sciencedirect-com.proxy1.library.jhu.edu/science/article/pii/S0166223606002001 Review article on mycochemicals https://pmc.ncbi.nlm.nih.gov/articles/PMC10647524/pdf/ijms-24-15596.pdf Evolutionary perspectives https://pmc.ncbi.nlm.nih.gov/articles/PMC4586293/pdf/nihms678801.pdf https://www.sciencedirect.com/science/article/abs/pii/S1087184523000439?via%3Dihub Recent Nature Medicine study https://www.nature.com/articles/s41591-025-03570-5

The vast majority of research on the cellular and molecular mechanisms of the storage and retrieval of memories has focused on the excitatory glutamatergic neurons that convey signals into and throughout the brain. However, recent research has revealed the importance of widespread oscillations in neural network activity (particularly gamma and theta frequencies) in cognition. In this episode Professor Dietmar Schmitz talks about features of short- and long-range neural connectivity and their roles in cognition with a focus on inhibitory GABAergic interneurons. Different subtypes of GABAergic neurons have different molecular signatures, shapes, electrophysiological properties, and connectivity patterns. These different GABAergic neurons serve specific functions in memory, and information processing. LINKS: Schmitz lab page: https://schmitz.neurocure.de/ GABAergic interneurons and memory: https://www.cell.com/action/showPdf?pii=S0896-6273%2823%2900475-0 microcircuits and spatial coding: https://journals.physiology.org/doi/epdf/10.1152/physrev.00042.2020 hippocampal CA3 module: https://pmc.ncbi.nlm.nih.gov/articles/PMC10861929/pdf/pnas.202312281.pdf

Research has shown that excessive dietary protein intake and high amounts of branch-chain amino acids (BCAA) in particular can accelerate aging and exacerbate chronic diseases of aging. In this episode University of Wisconsin Assoc. Professor Dudley Lamming talks about the cellular amino acid sensing mTOR pathway and its influences on aging and disease processes. The Lamming laboratory is making major contributions to establishing how amino acid intake affects cells and organ systems in health and disease. This research has important implications for optimizing health throughout the lifespan. LINKS Lamming lab webpage: https://lamminglab.medicine.wisc.edu/ Review article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9197406/pdf/ACEL-21-e13626.pdf Protein restriction in Alzheimer's mouse model: https://pmc.ncbi.nlm.nih.gov/articles/PMC11189507/pdf/41467_2024_Article_49589.pdf BCAA restriction, aging, and lifespan: https://pmc.ncbi.nlm.nih.gov/articles/PMC10655617/pdf/nihms-1939504.pdf

Dopamine is best known as a neurotransmitter involved in the experiencing of pleasure and reward, and for its role in addiction to drugs, gambling, food, etc. But dopamine is also very important in the brain's ability to evaluate computational tradeoffs (cost versus benefit) and make decisions. In this episode Roshan Cools a Professor of cognitive neuropsychiatry at Radbout University in the Netherlands talks about how dopamine normally controls the neuronal circuits in the striatum and prefrontal cortex that regulate motivation and cognitive control. By combining PET imaging to measure relative dopamine release with various cognitive control tasks and administration of drugs such as methylphenidate (Ritilin) that affect dopamine signaling she found that every individual has their own dopamine 'set point'. She talks about how dopaminergic drugs enhance cognitive control in ADHD patients but impair cognitive control in patients with Parkinson's disease. We also talk about potential pharmacological and behavioral modifications to optimize cognitive control in healthy people. LINKS Professor Cools web page: https://www.roshancools.com/ Chemistry of the adaptive mind: https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2930838-4 Dopamine's role in making cost versus benefit decisions: https://pmc.ncbi.nlm.nih.gov/articles/PMC8282630/pdf/nihms-1697802.pdf

In this episode I talk with Professor Maryanne Garry at the University of Waikato New Zealand about several interrelated realms of human cognition that are fundamental to changes in the behaviors of individuals and social groups as influenced by electronic media and artificial intelligence. Dr. Garry has devoted her career to understanding how memories of one's past experiences can be distorted, how false information can become engrained in one's system of beliefs. She talks about individual and collective memories, and the brain's source monitoring systems and how they are influenced by group identity, repetition of information (whether true or not). Interestingly although memories of untruths can be retracted when new information is provided they can still influence one's decision-making. She also talks about how social media and AI (LLMs) influence the brain's source monitoring systems and potential approaches to ameliorating their adverse effects on mental health and societal discord. LINKS Dr. Garry's lab webpage: https://www.garrylab.com/ Collective and autobiographical memories: https://www-tandfonline-com.proxy1.library.jhu.edu/doi/epdf/10.1080/09658211.2022.2154804 Retracted memories: https://pmc.ncbi.nlm.nih.gov/articles/PMC9365748/pdf/13421_2022_Article_1328.pdf LLMs and the institutionalization of misinformation: https://pdf.sciencedirectassets.com/271877/1-s2.0-S1364661323X00138/1-s2.0-S1364661324002213/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEG4aCXVzLWVhc3QtMSJGMEQCIA9kHgyXdZwhJDF2Nc6gQiDwWhuj%2F9fvysEcbyMKnaM8AiBEX6%2BAkbxOT%2FT%2FJCTkVCeOnibe%2Fin%2BeiHRN8auAjLO7yq8BQin%2F%2F%2F%2F%2F%2F%2F%2F%2F%2F8BEAUaDDA1OTAwMzU0Njg2NSIMnDX%2Bz%2BiS%2BD9b8%2BsCKpAFlPWcxi2Nu4wg%2FlKU8mSVoZQPyiR6LQkJokbH6TlJvixjI04Sd92Kj5SSAHB8QvzpkbIuJoErUOjgSlkpGTlKK7kMqkMt2S%2FSmUyp5OzH5PlhGyxSi3Lpq%2Bdjol9vmiF9rXTEeHeRrHzUh48X4HajvARh9q6lC6v%2FCSx84dpolcD3kMlhYIEuYfJbVc%2Fm4k%2F9xtjX2NtA3BhLHFs8nzUuuDcNtLxZ3mi7SLbQz9oBGMdeJFd2bBjf%2ByCpjqUl%2Bs9ALlI75kYC1aDPdB2f84XWB78f9CKz%2FtNob%2FjKE9tMcwB3Dni8%2FtndhQRjybd74siNn2sApJu%2FXKwgKsqJEvKP8CDYYTgnSVrRAseqXSdLKoA63G91ZG9K7nOjODivQI%2BpzciLPlvzYVjpeEJ5LE3PC5VVYxCkOQKUtwDvUgXigGtfHsgazln3m8WMBxakhHXrKEWK7q%2FuxuLBle%2BD%2BK%2FdM1aw2JpS7hyllAgfZ4cuSBexwzQ%2B3OjGg4Fe2MBdTmpa0ZG9WT7B7KNo2FxoiKEZJupQ3z%2FaMOIBCMCqa0EvuMCQpIqZKS8zxngNpJeOVpTuWv%2BJ3EQjM3T6GL9hxNA%2BszUz7MR7KN6so2RZvU32fCtHB14j2vHVXkaytDu653flfPWASPWQKprXowbOsghYz0UegMyUjO1a67axaYcTUrVAt7OxvM%2BwyZDkSPJhOWHDfcSyL30v%2BhTLjWxGRy4GdrEndVdgAw3RmjDWx0E4CrmUkycwWQND01xhJI6IijMO%2BgoJ%2FFVSnrNNvGVGCCtU80%2FylVKonMGKTDptdPrqsi8aQDdQYdyL5sq4itFXa6Obi0EvBTjlB8p%2BMORusgVwSP9PBJFbLLbT%2FnxegI2FJJ0wh5%2BMvgY6sgFhGU%2FH5TGFnQMV5o1J5r37XL5V8jHthF%2FO3kUtL%2Fk6oDRUfFYPQxvyRxi0EzFaGcDu7jYC53O%2BZxrzPgPJS1qP6%2BNJu6%2FDls8iyGvg3JAi85RLRRgZlhp3wnfLghXW4W6VnmXzQzMUdjCahckzzB9w8XVmhGrXw%2F4JIvHgSx73D6oVy%2BPMi4h%2F4I5T08ApqPSaR7bkrnYvAtWgfjRynIpiabV%2BBisHSuNwL11EsBTf3auq&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250301T144026Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY4USPLILK%2F20250301%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=03ec372fac008431242909cb94e0acfca84a8a7d4fdc142df102bf78149b9761&hash=1da48c96274cce2ef2914eaf9bd37a118e05e359da92f349fb5c1a767dcd852e&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1364661324002213&tid=spdf-52d87662-932c-46b0-925b-296bc39e2460&sid=f0d8a6a836dc5742e59bb5900fc7ac98a3f4gxrqa&type=client&tsoh=d3d3LXNjaWVuY2VkaXJlY3QtY29tLnByb3h5MS5saWJyYXJ5LmpodS5lZHU%3D&rh=d3d3LXNjaWVuY2VkaXJlY3QtY29tLnByb3h5MS5saWJyYXJ5LmpodS5lZHU%3D&ua=0f105a505f56585c0053&rr=919968d1f9843b0b&cc=us