Kepecs Lab @ WashU

Important topic, high potency THC is a different game.

Interesting proposal. How about editors using LLMs not to generate reviews, but to flag those that look generic and light on insight? And also use LLMs to cross-check reviews for factual errors, since some reviews can be confidently wrong.

Chairs and vice chairs for the Psychedelics GRC

We worked so well as a team for the #GRCPsychedelics @vyazovskiy.bsky.social @viditavaidya.bsky.social @melissaherman.bsky.social

and congrats to @theborislab.bsky.social and @mikaelpalner.bsky.social, who will be the future vice-chairs!

Meet Area Postrema!

I will fly to anywhere in the United States on my own dime to talk to people about basic science! I encourage all of you, particularly senior scientists to make this commitment. If you are looking for material ask @karalmarshall.bsky.social She has put together an amazing basic talk!

We'll miss you here Ilya! Exciting opportunity, congrats! Wishing you all the best for this next chapter!

Given all that is going on consider this quote from Bertram Russell's 1930 book The conquest of Happiness:
“The man who can be interested in the structure of atoms or the way in which a beetle navigates, is likely to get a joy in life which no amount of success in the pursuit of power can give. ”

💔 that’s really tough, so sorry

Thanks CJ!

14/ Finally, this work wouldn’t have been possible without generous support from many funders. Special thanks to the NIH, especially NIMH, NIDA, and the NIH Pioneer Award—for making long-term, high-risk neuroscience like this possible.
🧵🔚

13/ This builds on decades of work linking inflammation to fatigue, depression, and motivation loss. We’re picking up that thread, now with a defined brain circuit in play, a step toward circuit neuro-immunology.
#Inflammation #Depression #IL6 #Cancer #Cachexia #NeuroImmunology

12/ This project took a *huge* team, spanning neuroscience, immunology, and cancer. Grateful to co–first authors Aelita Zhu, Sarah Starosta, co–senior authors Marco Pignatelli & Tobias Janowitz & ours labs & all our amazing collaborators including @kravitzlab.com & Pavel Osten.

11/ We’re also excited about our effort-based tasks to measure motivation. Grounded in behavioral economics, they’re designed for cross-species computational psychiatry. We’re now adapting them for humans to bridge physical disease and psychiatric symptoms.

10/ Our work reframes cachexia: it’s not just body wasting, it inherently involves the brain. Chronic inflammation activates a neural circuit that suppresses motivation—likely
adaptive in acute illness but harmful when chronic, showing how physical disease directly causes psychiatric symptoms.

9/ We also used an IL-6–blocking antibody in mice—similar to FDA-approved drugs for rheumatoid arthritis. Given early, it improved survival. Given late, it still rescued apathy-like behavior. This points to a promising, translatable way to treat apathy in advanced disease.

8/ The circuit insights let us reverse apathy without stopping cancer:
— Knockdown of IL-6 receptors in area postrema
— Ablation of ArP→PBN neurons
— Boosting dopamine via optogenetics or dopamine agonist cocktail injected in nucleus accumbens.
Motivation was rescued even in late-stage disease.

7/ We used a patch foraging task with depleting rewards designed to measure effort sensitivity—grounded in behavioral economics. As cachexia progressed and IL-6 rose, dopamine in the nucleus accumbens fell. Mice gave up faster, even when rewards were still available.

6/ We mapped fill the circuit: IL-6 activates the area postrema neurons that project parabrachial nucleus and then to substanta nigra pr, which inhibits dopamine release in the nucleus accumbens. Optogenetic activation of ArP→PBN mimicked inflammation, rapidly suppressing motivation.

5/ To find the cause, we ran a cytokine screen and brainwide cFos mapping. The cytokine IL6 increased with cachexia. Most brain regions were suppressed, but a few lit up—most notably the area postrema, a circumventricular organ outside the BBB that could sense circulating IL-6.

4/ We tested in mice with cancer (C26 colon adenocarcinoma) and saw a striking loss of motivation.
As cachexia set in, effort sensitivity increased in two tasks—but mice still liked sweet rewards, showed no despair, and retained capacity to move. Apathy-like behavior.

3/ Apathy in cancer cachexia is often dismissed as a psychological reaction to physical decline. But what if it’s part of the disease process itself—driven by inflammation acting on the brain?

2/ Cachexia affects ~80% of late-stage cancer patients. It’s a wasting syndrome with severe weight/muscle loss despite eating. But it also drains the mind—patients lose motivation, withdraw from loved ones, and struggle with treatment. Apathy and fatigue take over.

A neuroimmune circuit mediates cancer cachexia-associated apathy Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depres...

1/ Why do patients with late-stage cancer lose motivation & sink into apathy?
🔥 Our new Science paper shows chronic inflammation activates a cytokine-sensing brain circuit that lowers motivation. Huge team effort: Aelita Zhu, Sarah Starosta, Pignatelli & Janowitz labs! 🧵
🔗 doi.org/10.1126/scie...

convergence!

Looking forward to reading it! Spot on

Subpopulations of neurons in lOFC encode previous and current rewards at time of choice A distinct subpopulation of neurons in the rat orbitofrontal cortex encodes reward history at the time of choice, providing a potential neural substrate by which reward history may influence decisions...

And @constantinoplelab.bsky.social and @carlosbrody.bsky.social found a functionally similar lOFC subpopulation in a different task, suggesting this is a conserved circuit motif:
elifesciences.org/articles/70129

Frontal cortex neuron types categorically encode single decision variables - Nature Frontal cortex neurons can be grouped into categorical response types corresponding to particular decision variables, such as reward size, decision confidence, or value, and individual variables may b...

We found that orbitofrontal to striatum projection neurons preferentially sustain information about prior outcomes between trials: www.nature.com/articles/s41...

So glad you're doing this, your voice is what the field needs! What I wish more people knew: pharma gave up on psychiatry because the science wasn’t ready. Finally, we can causally link brain circuits to symptoms. Real mechanism-based treatments are possible *if* we fund the science to get there.

I graduated high school in 1990. For this year's graduates, this music is to them what 60's music was to me when I was their age. Wild.

We sat in the opposite corner! In this end it turn into a great game.