Interoception is a term used to describe the processes by which the brain detects, interprets, and responds adaptively to signals (pain, hunger, fatigue, etc.) coming from various organs in the body. In this episode University of Pennsylvania neuroscientist Nick Betley talks about recent research that has revealed key roles for relatively small numbers of neurons in the hypothalamus in interoception. Using cutting-edge imaging and molecular genetic tools Betley and his colleagues have shown how specific hypothalamic neurons can turn off pain signals and suppress inflammation. These findings have important implications for the development of interventions that alleviate chronic pain Intriguingly, they recently discovered that activation of a group of hypothalamic neurons (SF1 neurons) occurs in response exercise and their activation is required for endurance to increase with training. These findings suggest enhancement of hypothalamic SF1 neuron activity might prevent muscle loss during aging or in certain diseases or physical disabilities.

LINKS Betley laboratory page:

https://web.sas.upenn.edu/betley-lab/

Exercise-induced activation of ventromedial hypothalamic steroidogenic factor-1 neurons mediates improvements in endurance.

https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900989-4

Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits.

https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2901350-5

A Neural Circuit for the Suppression of Pain by a Competing Need State.

https://www.cell.com/action/showPdf?pii=S0092-8674%2818%2930234-4

Normally activity in the brain's neural networks is tightly regulated by the interplay between neuronal excitation by the neurotransmitter glutamate and inhibition by GABA. An epileptic seizure is a dramatic example of what can happen when an abrupt excitatory imbalance occurs. However, excitatory imbalances also occur during aging and contribute to the dysfunction and degeneration of neurons in Alzheimer's disease. In this episode I talk with University of Washington Associate Professor Melissa Barker-Haliski about how neural network activity is normally regulated, the causes of hyperexcitability in neurological disorders, and the benefits and pitfalls of drugs that suppress neural network excitability.

LINKS

Barker-Haliski lab page:

https://sites.uw.edu/mhaliski/

Review articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11390315/pdf/nihms-2013484.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC9096090/pdf/fneur-13-833624.pdf

Original research articles:

https://www.sciencedirect.com/science/article/pii/S0014488625004510?via%3Dihub

https://journals.sagepub.com/doi/epub/10.1177/13872877251343321

https://onlinelibrary.wiley.com/doi/epdf/10.1111/epi.18395?saml_referrer

Stanford Professor Liqun Luo's laboratory investigates the mechanisms by which neural circuits in the brain are assembled during development and how this neuroarchitecture enables their functions throughout life. During the past 30 years his work has provided technical advances that enabled the establishment of roles for specific proteins in the formation of synaptic connections between individual neurons. In this episode I talk with Liqun about experiments using these technologies that revealed specific molecular codes on the surface of neurons that mediate either adhesive or repulsive interactions and thereby instruct synaptic partner matching during development neural circuits. Recent research in his laboratory has shown that the three-dimensional complexity of neural circuits in the olfactory system is achieved by serial reduction to one-dimensional projections. Professor Luo is a member of the National Academy of Sciences and author of "Principles of Neurobiology" a textbook widely used for undergraduate and graduate neuroscience courses.

LINKS

Luo lab webpage:

https://luolab.stanford.edu/

Review article on the architectures of neural circuits:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8916593/pdf/nihms-1746805.pdf

Article in Science on dimensionality reduction:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12614222/pdf/nihms-2120734.pdf

Article in Nature on repulsions and synaptic partner matching:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12804089/pdf/41586_2025_Article_9768.pdf

Article in Nature on altering an olfactory circuit by manipulating cell surface molecular codes:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12804075/pdf/41586_2025_Article_9769.pdf

The rapid psychedelic effects of the mushroom chemical psilocybin and its long-lasting mood-elevating effects are remarkable. While psilocybin and other psychedelics activate the serotonin 5HT2A receptor the nature of the functional and structural changes responsible for the dramatic effects of psychedelics on perception, mood, and cognition are unknown. In this episode Cornell University Professor Alex Kwan talks about very recent research in his laboratory showing that psilocybin triggers long-lasting changes in the structure of certain neural networks in the brain that may explain the neuropsychological effects of psychedelics.

LINKS

Kwan lab at Cornell

https://alexkwanlab.org/

Review article in Nature Reviews Neuroscience:

file:///Users/markmattson/Downloads/s41583-024-00876-0%20(1).pdf

Article in Nature:

file:///Users/markmattson/Downloads/s41586-025-08813-6%20(2).pdf

Article in CELL:

https://www.cell.com/action/showPdf?pii=S0092-8674%2825%2901305-4

Here I describe evidence that brain aging can be slowed by lifestyle choices that include exercise, moderation in energy intake, and consumption of plant-based diets.

LINKS

https://pmc.ncbi.nlm.nih.gov/articles/PMC5913738/pdf/nihms958771.pdf

https://www.cell.com/action/showPdf?pii=S1550-4131%2823%2900473-4

In this episode I talk with Case Western Reserve University Professor Andrew Pieper about how it might be possible to restore neuroplasticity and cognition in Alzheimer's disease. The conversation focuses on a recently published study from his laboratory which shows that a chemical called P7C3-A20 that restores energy balance in brain cells can reverse brain pathology and restore cognitive function in a mouse model of Alzheimer's disease.

LINKS

Pieper laboratory:

https://www.harringtondiscovery.org/about/harrington-investigators/andrew-pieper-lab

Article discussed in this podcast:

https://www.cell.com/action/showPdf?pii=S2666-3791%2825%2900608-1

In this lecture I describe how changes occurring in the brain during normal aging set contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Cellular and molecular hallmarks of aging predispose brain cells to neurodegenerative orders with environmental and genetic factors determining if and when the disease manifests.

LINKS:

Review articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC3710114/pdf/nihms288391.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC7948516/pdf/nihms-1624328.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC9242841/pdf/nihms-1685119.pdf

During the past decade several new technological advances have enabled the identification of ensembles of neurons that encode a specific memory trace (engram cells) and for controlling the activity of engram cells so that recall or inhibition of a memory is controlled by the experimenter. The technologies include fluorescence 'tagging' of engram cells and optogenetic activation or inhibition of the engram cells. In this episode professor Tomás Ryan talks about these developments and his own research which provides evidence that memory recall involves competition between different engrams, that forgetting a memory is an active process in which recall of the memory is suppressed. Studies of amnesia have shown that memory engrams can still exist and can be recalled by electrical stimulation.

LINKS

Review and Perspective articles

https://www.cell.com/action/showPdf?pii=S0166-2236%2825%2900153-5

file:///Users/markmattson/Downloads/s41583-021-00548-3%20(1).pdf

Engram cell connectivity and memory

https://www.cell.com/action/showPdf?pii=S0960-9822%2823%2901512-9

Forgetting and engram expression

https://pmc.ncbi.nlm.nih.gov/articles/PMC11537488/pdf/elife-92860.pdf

Recent discoveries show that some neurodegenerative disorders occur because of abnormalities in the processing of RNA in the cell nucleus and/or its export from the nucleus. Johns Hopkins University Associate Professor Shuying Sun is at the forefront of research that is establishing the molecular mechanisms responsible for RNA dysregulation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Her research is contributing to a rapid acceleration of understanding of the causes of ALS and FTD and to the development of new pharmacological and gene therapy-based treatments for these disorders.

LINKS

Dr. Sun's laboratory webpage:

https://sunlab.jhmi.edu/

Review article

https://pmc.ncbi.nlm.nih.gov/articles/PMC11790913/pdf/44318_2024_Article_352.pdf

Original research articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC5754368/pdf/41467_2017_Article_2495.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC6895427/pdf/nihms-1539444.pdf

https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1

https://www.biorxiv.org/content/10.1101/2025.09.30.679260v1

https://www.biorxiv.org/content/10.1101/2025.06.13.659508v1

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel.

This episode begins by highlighting recent evidence showing adverse effects on the brain of excessive activation of the mTOR pathway as a consequence of dietary branched chain amino acid consumption. Then I describe evidence that Beyond the age of 40 years brain aging results in progressive decrements in function which are associated with reductions in gray matter and synapse numbers particularly in brain regions that play critical roles in memory, executive functions, and task switching. Recent progress has been made in identifying molecular markers of brain aging in samples of blood or cerebrospinal fluid heralding a better understanding of factors that accelerate or retard brain aging. This episode reviews some of the salient research in these areas.