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

Vision loss is a major cause of disability throughout the world. While there are effective treatments for cataracts and for preventing glaucoma, there are numerous genetic disorders that cause degeneration of cells in the retina for which no treatments currently exist. Inherited retinal diseases can be caused by recessive (loss-of function) or dominant (gain-of-function) mutations in genes expressed in photoreceptor cells or retinal pigmented epithelial (RPE) cells. Dominik Fischer, a professor of ophthalmology at the University of Oxford has been working to develop gene therapies for several of these diseases. One remarkable example of success is voretigene neparvovec which is essentially the RPE65 gene in an adeno-associated virus which is injected into the retina between the photoreceptors and the RPE cells. The RPE65 gene encodes an enzyme generates 11-cis-retinol which is necessary for visual pigment (opsin) regeneration. More than 1000 patients with loss-of-function RPE65 mutations and severe vision loss have been treated with many experiencing improvement in vision, particularly those treated in earlier stages of retinal degeneration highlighting in the importance of genetic screening and early intervention. Preclinical and clinical trials of gene therapies for other inherited retinal diseases are in progress.

LINKS

Dr. Fischer's University of Oxford profile:

https://www.ndcn.ox.ac.uk/team/dominik-fischer

Articles related to the subject matter of this episode:

https://karger.com/ore/article/66/1/179/835297/Gene-Therapy-for-Inherited-Retinal-Disease-Long

https://pmc.ncbi.nlm.nih.gov/articles/PMC8421966/pdf/atm-09-15-1278.pdf

It is well-established that neurons have a high energy (ATP) demand and that mitochondrial impairment can render neurons vulnerable to degeneration. However, surprisingly little is known about the involvement of mitochondria in the activation and plasticity of individual synapses. In this episode Vidhya Rangaraju, head of the Neuroenergetics Laboratory at the Max Planck Florida Institute for Neuroscience, talks about her research on mitochondria and ATP in presynaptic axon terminals and postsynaptic dendrites and their roles in presynaptic vesicle cycling and postsynaptic dendritic spine plasticity. Elucidation of roles for mitochondrial dynamics and signaling in synaptic compartments will advance an understanding of mechanisms of synaptic plasticity in the healthy brain and of dysfunction and degeneration of synapses in neurodegenerative disorders.

LINKS

Rangaraju laboratory:

https://rangarajulab.org/

Research findings discussed in this episode

https://www.cell.com/action/showPdf?pii=S0092-8674%2814%2900013-0

https://www.cell.com/action/showPdf?pii=S0092-8674%2818%2931627-1

https://pmc.ncbi.nlm.nih.gov/articles/PMC10766606/pdf/41467_2023_Article_44233.pdf

https://www.biorxiv.org/content/10.1101/2025.04.09.648032v1

https://pmc.ncbi.nlm.nih.gov/articles/PMC12407993/pdf/nihpp-2025.08.27.672715v1.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC4091730/pdf/nihms596598.pdf

How does the brain rapidly integrate information coming our different senses with stored information, and their saliences, so as to make decisions and respond (or not)? In this episode I talk with UCLA Professor Lucina Uddin who investigates the relationships between connectivity of different brain regions and cognition with an emphasis on brain development and disorders thereof. In this episode I talk with Lucina about the insular cortex and evidence that it functions as a gatekeeper to neural networks distributed throughout the cerebral cortex including those in: the frontal and parietal cortexes that are known to mediate higher order executive functions and goal-directed behaviors; the default mode network (involved in 'mind-wandering' and self-reflection); and the salience network which includes connections with the anterior cingulate cortex and subcortical circuits involved in emotional processing. Professor Uddin has summarized the overall functions of the insular cortex as follows "The microanatomy and large-scale connectivity of the insular cortex positions it to play a critical role in triaging and integrating internal and external multisensory stimuli in the service of initiating higher-order control functions. Multiple lines of evidence scaffold the novel hypothesis that, as a key hub for integration and a lever of network switching, the anterior insula serves as a critical gatekeeper to executive control."

LINKS

The Uddin Laboratory: https://teams.semel.ucla.edu/bccl

Review article on the insular cortex: https://www.sciencedirect.com/science/article/pii/S0149763422002251?via%3Dihub

Additional relevant articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8491685/pdf/bhab156.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC7785575/pdf/nihms-1610276.pdf

The amyloid precursor protein (APP) is a transmembrane protein and the source of the amyloid beta-peptide that accumulates in plaques in the brain in Alzheimer's disease. However, the normal function(s) of APP are uncertain. In this episode I talk with Bassem Hassan, a developmental neurobiologist and molecular biologist at the Paris Brain Institute who has made major contributions that advance an understanding of the functions of specific genes in the processes of neurogenesis and the formation of neural networks. His research has provided evidence that APP normally functions in the regulation of brain development by influencing neuron progenitor cell proliferation and differentiation, and axon growth. These effects of APP on brain development involve facilitation of the well-known Wnt signaling pathway. Such findings suggest that genetic aberrancies that result in brain disorders such as Alzheimer's and Parkinson's may result from alterations in brain development that predispose to disease manifestation later in life.

LINKS

About Dr. Hassan:

https://parisbraininstitute.org/collaborators/hassan-bassem

Dr. Hassan's publications: https://scholar.google.com/citations?user=F8ExcEsAAAAJ&hl=en&oi=ao

Articles on APP function discussed in this podcast:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10275593/pdf/sciadv.add5002.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC8437438/pdf/elife-69199.pdf

https://journals.biologists.com/dev/article/141/13/2543/46288/Amyloid-precursor-protein-and-neural-development?guestAccessKey=

https://journals.physiology.org/doi/epdf/10.1152/physrev.1997.77.4.1081

There are about 100 billion neurons and 100 trillion synaptic connections between them in the human brain. The activity of those neural networks is controlled by only a handful of major neurotransmitters and all neurons respond to the excitatory transmitter glutamate and the inhibitory neurotransmitter GABA. This poses a major problem for using drugs that block or activate neurotransmitter receptors in understanding the function of specific circuits within and between brain regions and for treating neurological disorders. Ideally, the experimental neuroscientist wants to precisely control the activity of specific circuits of interest and the clinician wants to normalize the activity in dysfunctional circuits without altering the function of other circuits. Dr. Michael Tadross at Duke University has recently developed an ingenious solution to the problem of targeting selected neuron types with drugs – a technology called DART (drugs acutely targeted by tethering). In this episode Mike talks about his career path and how DART can be used to advance an understanding the function of specific neural circuits and may be used to restore brain function in disorders such as Parkinson's disease.

LINKS

Tadross laboratory: https://www.tadrosslab.com/tadross

Deconstructing behavioral neuropharmacology with cellular specificity: https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.aaj2161

DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity.: file:///Users/markmattson/Downloads/s41592-024-02292-9.pdf

Natural phasic inhibition of dopamine neurons signals cognitive rigidity: https://pmc.ncbi.nlm.nih.gov/articles/PMC11100816/pdf/nihpp-2024.05.09.593320v2.pdf