Opponent control of reinforcement by striatal dopamine and serotonin

Daniel F. Cardozo Pinto, Matthew B. Pomrenze, Michaela Y. Guo, Gavin C. Touponse, Allen P. F. Chen, Brandon S. Bentzley, Neir Eshel and Robert C. Malenka ()
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Daniel F. Cardozo Pinto: Stanford University School of Medicine
Matthew B. Pomrenze: Stanford University School of Medicine
Michaela Y. Guo: Stanford University School of Medicine
Gavin C. Touponse: Stanford University School of Medicine
Allen P. F. Chen: Stanford University School of Medicine
Brandon S. Bentzley: Magnus Medical
Neir Eshel: Stanford University School of Medicine
Robert C. Malenka: Stanford University School of Medicine

Nature, 2025, vol. 639, issue 8053, 143-152

Abstract: Abstract The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning1–8. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations9–14. However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here we establish a mouse model that enables simultaneous genetic access to the brain’s DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signalling and decrease 5HT signalling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioural deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive the acquisition of new associations and supported reinforcement more potently than either manipulation did alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

Date: 2025
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DOI: 10.1038/s41586-024-08412-x

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