Brain Ponderings podcast with Mark Mattson

Appetite (hunger and satiety) is controlled by neural circuits in the brain – particularly in the hypothalamus – and their reciprocal connections to peripheral organs involved in energy metabolism (gut and liver). Understanding the structural organization of these circuits (their synaptic connections) and their neurochemistry (particularly which neurotransmitters are used at which synapses) is of fundamental importance for human health and developing new treatments for metabolic disorders such as obesity and diabetes. Neuroscientist Henning Fenselau at the Max Planck Institute and University of Cologne Germany has made several major discoveries about how food intake and energy metabolism are regulated and the consequences of abnormalities in the underlying neural circuits. Among his recent findings concern how GLP-1 in the gut communicates with the brain via the vagus nerve, and the roles of specific synaptic signals (NPY, opioids, TRH, and GABA).   LINKS Fenselau laboratory page: https://www.sf.mpg.de/research/fenselau   GLP-1, the vagus nerve, hunger, and sugar metabolism: https://www.cell.com/action/showPdf?pii=S1550-4131%2821%2900219-9 Synaptic amplifier of hunger: https://pmc.ncbi.nlm.nih.gov/articles/PMC10160008/pdf/nihms-1882224.pdf Opioids and sugar appetite https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.adp1510 Brainstem – amygdala circuit during fasting https://pmc.ncbi.nlm.nih.gov/articles/PMC11211344/pdf/41467_2024_Article_49766.pdf

One of the most remarkable feats of biological ‘wizardry’ in the animal kingdom is the ability of some cephalopods (octopuses, squids, and cuttlefish) to rapidly change the color, patterning, and texture of their skin so as to blend in with their background. They accomplish these feats through the linking of neural circuits in the visual system and brain to muscle cells that control the dispersion of pigment in specialized skin cells called chromatophores. But the details of the neural circuitry and the computational processes that control the camouflaging process remain largely unknown. In this episode Columbia University neuroscientist Tessa Montague talks about her research on the neurobiology of camouflage and the many challenges that must be overcome to better understand this remarkable phenomenon.  LINKS Dr. Montague’s cuttlefish lab webpage: Tessamontague.com Links to camouflaging cephalopods https://www.youtube.com/watch?v=XocHDvHlcJM https://www.youtube.com/watch?v=Ojb1pxcSr5E Articles on the neurobiology of camouflage https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2901182-X https://www.sciencedirect.com/science/article/pii/S0959438824000382?via%3Dihub https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2900757-1

During vigorous exercise lactic acid (lactate) levels increase in the blood and during fasting and extended exercise the levels of the ketone BHB (b-hydroxybutyrate) increase. In this episode I talk with Stanford University professor Jonathan Long about his recent discovery that lactate and BHB in the blood are bound to the amino acid phenylalanine and that they (Lac-Phe and BHB-Phe) have beneficial effects on metabolic and brain health. Lac-Phe levels increase markedly in response to exercise in mice, humans, and race horses. Peripheral administration of Lac-Phe in suppresses food intake and reverses diet-induced obesity and insulin resistance in mice.  Genetic ablation of Lac-Phe biosynthesis causes hyperphagy and obesity even in exercising mice showing a critical role for Lac-Phe in the beneficial effects of exercise. BHB-Phe has similar effects on food intake and metabolic health. We talk about the potential benefits of Lac-Phe and BHB-Phe for brain health and resilience.  LINKS The Long laboratory webpage:  https://longlabstanford.org/ Lac-Phe articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC9767481/pdf/nihms-1852727.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10635077/pdf/nihpp-2023.11.02.565321v1.pdf BHB-Phe article:  https://www.cell.com/action/showPdf?pii=S0092-8674%2824%2901214-5

White matter consists of bundles of long axons that convey information between neural circuits between different brain regions within and between brain hemispheres. These long axons are wrapped with many layers of lipid-rich membranes of oligodendrocytes (a type of glial cell) and it is this ‘insulation’ that enables rapid propagation of signals over long distances.  The axons in white matter consume high amounts of energy and their energy demand increases during extended physical exercise. In this episode Professor Carlos Matute talks about his interesting journey to become a neuroscientist and his fascinating discoveries concerning the function and dysfunction of oligodendrocyte neurobiology. He and his team recently provided evidence that the lipids in myelin are consumed by neurons in marathon runners during the event and then are replenished during their recovery. We also talk about how oligodendrocytes and axons in white matter are damaged by traumatic brain injuries, stroke, multiple sclerosis, and neurodegenerative disorders.   LINKS About Carlos Matute https://www.achucarro.org/director/carlos-matute/   White matter and marathon running https://pmc.ncbi.nlm.nih.gov/articles/PMC12021653/pdf/42255_2025_Article_1244.pdf   Review articles https://pmc.ncbi.nlm.nih.gov/articles/PMC10454078/pdf/ijms-24-12912.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC4493393/pdf/fnana-09-00092.pdf

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