The Betley Lab at UPenn

Thanks also to Mark Hargreaves, Dayu Lin, and Alan Watts for insightful comments and their time to meet with Bethany.

Want to get stronger? Your brain may matter more than muscles, new research shows Studies on the neurons of mice suggest our own human endurance may have more to do with the brain than our physique.

Excited to share a recent national geographic article on the brain and exercise that highlights our research! Super grateful to Bethany Brookshire for her enthusiastic, tireless, and thoughtful article.

www.nationalgeographic.com/health/artic...

No brain, no gain: Neuronal activity enhances benefits of exercise | Penn Today Research led by Penn neuroscientist J. Nicholas Betley and collaborators finds that hypothalamic neurons are essential for translating physical exertion into endurance, potentially opening the door to...

Thanks to Nathi Magubane and the Penn Today team for the write up on our recent study!

We are excited to see where this leads!

penntoday.upenn.edu/news/no-brai...

Exercise-induced activation of ventromedial hypothalamic steroidogenic factor-1 neurons mediates improvements in endurance Kindel et al. show that repeated exercise potentiates the activity of ventromedial hypothalamic SF1-expressing neurons. SF1 neural activity is required for mice to achieve the endurance benefits of ex...

Read the full report 📄 www.cell.com/neuron/fullt...
DOI: 10.1016/j.neuron.2025.12.033
Congrats to first authors Morgan Kindel & Ryan Post + all collaborators!
#Neuron #Neuroscience #Exercise

After training, increasing SF1 neuron activity can push performance beyond the typical endurance plateau. Could this be a potential target of “exercise-mimetics”?

With repeated training, this VMH SF1 circuit strengthens (anatomically + physiologically).
This increase in post-exercise activity of SF1 neurons is required for endurance improvements.

VMH SF1 neurons are activated during running AND they stay active after exercise.
That sustained post-exercise signal is a key driver of training benefits.

Endurance gains aren’t just muscle/heart/lung adaptations.
We find the brain is a critical intermediate in how training rewires the body.

🧠🏃 New in Neuron (open access): “Exercise-induced activation of VMH SF1 neurons mediates improvements in endurance”

Finally able to share what we learned about the brain & exercise 🧵

Tomorrow, we will be sharing with the world, some of what we have learned about how the hypothalamic activation effects metabolism and adaptation after exercise! Stay tuned…

We found a massive upregulation of neural activity (via Fos) throughout the brain! In the video below, you can see the brainwide changes observed in an exercised animal compared to a sedentary control. Some regions of interest to our lab are highlighted.

This is your brain.
This is your brain on exercise.
This dataset collected over 5 years ago captivated our neuroscience lab.

What’s brewing in the Betley Lab at UPenn? ☕️🧠 Thrilled to welcome Elisa Caffrey! Elisa studies fermented foods and the microbes/metabolites they produce—how do they shape our bodies and brains after we eat? Excited for this new frontier!

lways fun to collaborate with the Thaiss Lab and excited about what is coming next. If you are interested in how the gut rapidly transduces health signals to the brain, read the review: authors.elsevier.com/c/1mUfe3BtfH... #gutbrainaxis #interoception

Therapeutic outlook: “interoceptomimetics” = molecular interventions that stimulate the right body↔brain signaling with the goal of restoring homeostasis.

When interoception breaks, disease risk rises. Disrupted body→brain feedback loops appear across many conditions (not just GI).

Environment + lifestyle shape these circuits. What we eat, when we eat, and other exposures can recalibrate gut→brain signaling over time.

Many of these messages are rapid. Sensory pathways (alongside endocrine + immune routes) help the brain keep a running readout of internal state and adjust appetite, metabolism, inflammation, and other systems accordingly.

The gut is the body’s biggest interface with the outside world. It samples dietary nutrients, microbial metabolites, hormones, neurotransmitters, immune cues (and more)… then converts that information into gut→brain messages.

The gut isn’t just for digestion. It is a sensory organ that reports our internal state to the brain in real time. Our Neuron review explores “intestinal interoception”: how gut signals tune physiology + behavior.

Thanks to all of our collaborators and funding and congratulations to all the authors who were a fantastic team. In particular, Nitsan Goldstein for the creativity and determination that were vital to this entire project and publication.

Implications? We think persistent Y1R neural activity represents a neurophysiological signature of enduring pain and can be used as a physiological biomarker for therapies designed to reduce chronic pain.

With Amadeus Maus and Ann Kennedy, we built a model to quantify pain-state in animal models. Animals perform coping behaviors to alleviate perceived pain. This model shows persistent Y1R neural activity resembles modeled pain and competing need signals integrate at Y1R neurons to reduce pain.

We identified multiple ‘pain-killing’ circuits in the brain that suppress pain by release of NPY in the PBN. Thus the brain has an efficient, tunable biological system whereby increased NPY in the PBN suppresses lasting pain.

These Y1R neurons are anatomically and molecularly heterogeneous – instead they form a functionally defined ensemble that transcends discrete molecularly and anatomically defined populations.

In the study we found neurons in the hindbrain (Y1R neurons) that broadcast a message of enduring pain state. These neurons may underlie the chronic unpleasantness of pain that is a widespread clinical problem.

A parabrachial hub for need-state control of enduring pain - Nature Activity in a set of parabranchial neurons in the mouse brain is increased during chronic pain, predicts coping behaviour, and can be modulated by circuits activated by survival threats.

Out today – our newest study on how the brain processes and filters signals of pain!
www.nature.com/articles/s41...
Summary written by Nathi Magubane
penntoday.upenn.edu/news/its-all...

Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain…

Read more about our discoveries:
www.sciencedirect.com/science/arti...
www.nature.com/articles/s41...

#ExercisePhysiology #Neuroscience #BrainHealth #MetabolicHealth #Collaboration #Research #BetleyLab

What's next for the #BetleyLab? We're diving deep into #EXERCISE! 🏃‍♀️💪
Our emerging studies show exercise doesn't just change your body – it literally rewires brain circuits and impacts #dopamine response. It’s a whole new world of #body-brain interaction. Stay tuned !

or what the NIH transmitter had to say about it here: www.nih.gov/news-events/...