While it has long been known that activity in neural networks in sleep differs from activity during waking hours. EEG recordings have revealed patterns of activity oscillations associated with deep (non-REM) sleep and rapid eye movement (REM) sleep. However, it remains unclear how transitions from wake to sleep and from sleep to wake are controlled. One hypothesis is that there are sleep-inducing substances that accumulate during waking hours and then reach a certain tipping point that causes sleep. However, such a sleep substance has not been identified. Genes regulating the cellular circadian clock are implicated but operate on too slow a time scale to explain wake – sleep and wake – sleep transitions. University of Tokyo professor Hiroki Ueda has accumulated evidence for a different mechanism of sleep regulation in which calcium functions as a master regulator by virtue of its effects on phosphorylation of ion channels that regulate neuronal excitability. In this episode I talk with Hiro about his elegant experiments that use cutting-edge technologies to manipulate calcium-regulated kinases (CaMKII alpha and beta) in forebrain neurons while quantifying sleep and wakefulness by continuous monitoring of breathing patterns. Hiro also talks about the development in his laboratory of next generation single-cell genetics and whole-brain single cell imaging technologies and their broad applications in neuroscience research.

LINKS Review articles https://www.sciencedirect.com/science... https://pmc.ncbi.nlm.nih.gov/articles...

Whole brain single-cell atlas of neural activity https://www.science.org/doi/10.1126/s...

Competition between kinases and phosphatases in sleep-wake cycles https://www.nature.com/articles/s4158...

In this episode I talk with Weill Cornell Medicine professor Tim Ryan about the local regulation of energy metabolism in synapses. Tim and his colleagues use high resolution imaging of fluorescent probes that enable measurements of ATP and calcium in presynaptic terminals and postsynaptic dendrites of neurons in which energy substrates are manipulated. His lab has made several novel findings that refute previous assumptions concerning energy metabolism in neurons. Examples, include that neurons can store glycogen and triglycerides, and that free fatty acids and the ketone beta-hydroxybutyrate can fuel synapses and support neurotransmission. We also talk about gaps in understanding of the mechanistic links between calcium influx and energy metabolism in synapses, and the involvement of impaired synaptic energy metabolism in aging and neurodegenerative disorders.

LINKS

Tim Ryan laboratory page: https://sites.google.com/site/ryanlab1/Home

Articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC5675126/pdf/nihms882178.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12286841/pdf/42255_2025_Article_1321.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC11185772/pdf/nihpp-2024.06.08.598077v1.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12718339/pdf/pnas.202523019.pdf

In Alzheimer's disease and other 'Tauopathies' the Tau protein (which normally controls the polymerization of microtubules) becomes hyperphosphorylated and self-aggregates into insoluble fibrils called 'neurofibrillary tangles' within neurons. Excessive phosphorylation of Tau by a kinase called GSK3 is implicated in neurofibrillary tangle formation and neuron death in Alzheimer's disease. The Spanish biochemists Felix Hernandez and Jesus Avila made seminal discoveries concerning Tau tangle chemistry. In this episode I talk with Felix about that work and its importance for understanding, preventing, and treating Tauopathies. Interestingly, lithium (the third element on the periodic table) has long been known to be an effective treatment for bipolar disorder and more than 20 years ago Felix and his colleagues showed that lithium treatment prevents tau hyperphosphorylation and neurofibrillary tangle formation in a mouse model of frontotemporal dementia. Very recent findings from another laboratory suggest that low levels of lithium in the brain may be a risk factor for Alzheimer's disease. Clinical trials of lithium for tauopathy patients in the early stages of the disease are in progress.

LINKS

Felix and Jesus laboratory website:

https://www.cbm.uam.es/index.php/scientific-programs/physiological-and-pathological-processes/molecular-neuropathology/tau-function-and-dysfunction-in-alzheimer-disease/

Key articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC140191/pdf/cde013.pdf

https://pubmed.ncbi.nlm.nih.gov/17059563/

https://pubmed.ncbi.nlm.nih.gov/14624025/

https://pubmed.ncbi.nlm.nih.gov/40770094/

Ultraprocessed foods that contain high amounts of simple sugars (particularly high-fructose corn syrup), saturated fats, salt, and various chemicals that enhance taste and color. In this episode I talk with University of Michigan psychology professor Ashley Gearhardt about research showing that ultraprocessed foods are addictive and a major cause of poor metabolic health and chronic diseases in the United States and many other countries. Ashley developed a clinical metric of food addition – the Yale Food Addiction Scale – which her lab and others have used to understand the neurobiology and psychology of ultraprocessed food addiction. Ashley has been active in a wide array of issues surrounding ultraprocessed foods including ultraprocessed food industry tactics, government regulations, legal issues that follow logically from this country's experience with tobacco and opioid addiction, and solutions.

LINKS

https://www.fedupmovement.org/

https://ajph.aphapublications.org/ultraprocessedfoodssection

https://unjunkedfood.substack.com/

https://www.thelancet.com/series-do/ultra-processed-food

In this episode – a role reversal. Mark is interviewed by Justin Lathia a professor at the Cleveland Clinic and former graduate student in Mark's lab. The podcast provides a whirlwind tour of Mark's early life and research career – from graduate and postdoc training in Iowa and Colorado, to research in his laboratories at the University of Kentucky and the National Institute on Aging. Justin also queries Mark on a range of topics including: advice for graduate students; major technological advances; the promises and perils of AI; the current state of neuroscience and society; his heroes of science; and what he is doing these days.

LINKS:

Interview with Neuron: https://www.cell.com/action/showPdf?pii=S0896-6273%2821%2900116-1

Google scholar: https://scholar.google.com/citations?user=N3ObarMAAAAJ&hl=en&oi=ao

Research.com list of best neuroscience scientists 2026: https://research.com/scientists-rankings/neuroscience

The combined efforts of neurologists, geneticists, molecular biologists, and electrophysiologists have identified genes in which rare mutations cause either extreme pain sensitivity or complete lack of pain sensation. The extreme pain syndromes include primary erythromelalgia and small fiber neuropathies that result painful extremities triggered pressure, touch, and heat. Three of these genes encode sodium ion channels called Nav1.7, Nav1.8, and Nav1.9. Additional genes associated with pain disorders are also being identified and studied. In this episode I talk with University of Oxford professor David Bennett about how research on these patients and their gene mutations have led to the development of a non-addictive and highly effective drug for severe pain that selectively blocks the Nav1.8 sodium channel. Drugs that block Nav1.7 or Nav1.9 are currently being developed. This is a remarkable example of how identification of rare genetic causes of a disorder have resulted in the development of drugs that can help reduce the suffering of everyone.

LINKS

Dr. Bennett's Oxford web page:

https://www.ndcn.ox.ac.uk/team/david-bennett

Articles related to this podcast:

https://journals.physiology.org/doi/epdf/10.1152/physrev.00052.2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC4251302/pdf/practneurol-2013-000758.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC9991512/pdf/fcad037.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC5828379/pdf/jop-159-469.pdf

Optimal health depends critically on maintenance of an evolutionarily ancient circadian clock that ticks within all cells of the body and brain. Discovery of the genes that encode the core proteins of the molecular clock have revealed how the clock works and, importantly, how the clock influences health and resilience. Joseph Takahashi discovered the gene for CLOCK which is one of four proteins that control circadian rhythms. In this episode I talk with Joe about his discoveries concerning how the molecular clock functions, how the clock influences energy metabolism, the consequences of disruption of the clock for health, and how we can improve our circadian rhythms by, for example, daily time-restricted eating.

LINKS

Takahashi laboratory

https://labs.utsouthwestern.edu/takahashi-lab

How the cellular circadian clock works

https://pmc.ncbi.nlm.nih.gov/articles/PMC10631358/pdf/nihms-1930368.pdf

Daily time-restricted eating and circadian rhythms

https://www-annualreviews-org.proxy1.library.jhu.edu/docserver/fulltext/10.1146/annurev-nutr-112525-011241/annurev-nutr-112525-011241.pdf?expires=1779798437&id=id&accname=ar-223467&checksum=908E9889190B85725CE892E63BB5413C

In this episode I talk with MIT neuroscientist Ev Fedorenko about the neural networks that process language in the human brain, the relationships between the processing of language and thought, evolutionary perspectives on thinking versus communicating, and artificial intelligence systems as tools for advancing understanding of the neurobiology of language. To understand the neural networks of language and their relationships with networks for cognition, perception, and motor systems the Fedorenko lab uses fMRI, intracranial recordings, EEG, behavioral experiments, and computational modeling. Her research includes studies of development of the language network, and the effects aging, aphasias and other neurological disorders on the networks.

LINKS

Dr. Fedorenko's laboratory:

https://www.evlab.mit.edu/

Recent review and perspective articles:

https://www.nature.com/articles/s41586-024-07522-w

https://www.annualreviews.org/docserver/fulltext/neuro/47/1/annurev-neuro-120623-101142.pdf?expires=1778850274&id=id&accname=guest&checksum=846F655794ACA01CB4739ABEA17B4B1C

https://www.nature.com/articles/s41583-024-00802-4