Congrats James!

@mcherrygarcia.bsky.social
@michaelaguo.bsky.social

Special thanks Michaela Guo who co-led this project as an undergrad/RA and is now MD-PhD bound! I was lucky to work with her and can't wait to see what she does next.

And thank you to the rest of the team: Wade Morishita, Matt Pomrenze, Neir Eshel, and Rob Malenka

8/n

We think this provides one putative mechanism to explain longstanding observations of serotonin counteracting dopamine's rewarding effects.

Our work also provides a characterization of the mesolimbic serotonin system that we hope will be resource for the field.

7/n

Finally we tested whether this also happens in vivo. We used DAT (bup) and SERT (esc) blockers to upregulate dopamine or serotonin and labeled cfos as a proxy for neural activity.

‼️ Enhancing dopamine activity preferentially activated D1-MSNs while enhancing serotonin activated D2-MSNs

6/n

This suggested that serotonin may differentially modulate D1 and D2 MSN activity in a manner opposite to their regulation by dopamine. To test this, we recorded from genetically identified D1 and D2-MSNs.

⬆️⬇️ Dopamine selectively excited D1-MSNs while serotonin selectively activated D2-MSNs

5/n

Next we used RNAscope to map the their distribution.

📊 expression varied across subregions and cell-types for every gene examined

❗️ Overall though, D1-MSNs expressed a mix of Gi, Gs, and Gq coupled serotonin receptors while D2-MSNs were enriched for receptors in the Gq coupled 5HT2 family

4/n

To answer this question, we first determined which serotonin receptors are expressed on striatal MSNs.

🎯 Mining a scRNA-Seq dataset revealed that >90% of MSNs express serotonin receptors, and that this is primarily limited to a subset of ~8 receptor genes

3/n

📚 It's known that dopamine drives reinforcement via differential modulation of D1 and D2 MSNs, and last year we showed serotonin counteracts dopamine's reinforcing effects.

This inspired us to ask:

❓How does serotonin affect striatal neuron activity?

2/n

Thank so much! Hope you're doing well!!

Thank you!!

Thank you!

Thank you!