A conserved population of genetically defined striatal neurons gates opioid reward

Drake, O. R.; Fiore, C. M.; Jorgensen, E. T.; Newman, C. E.; Potter, L. A.; Trull, A.; Pradeep, A.; Ianov, L.; Peters, J.; Heinsbroek, J. A.; Day, J. J.

doi:10.64898/2026.07.28.741269

bioRxiv · 10.64898/2026.07.28.741269

A conserved population of genetically defined striatal neurons gates opioid reward

Drake, O. R.·Fiore, C. M.·Jorgensen, E. T.·Newman, C. E.·Potter, L. A.·Trull, A.·Pradeep, A.·Ianov, L.·Peters, J.·Heinsbroek, J. A.·Day, J. J.

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Abstract

A longstanding paradox in striatal circuit architecture is that opioid reward depends on -opioid receptors ({micro}ORs) in nucleus accumbens medium spiny neurons (MSNs), yet {micro}OR function is not explained by the canonical D1/direct and D2/indirect pathway organization. Here, we identify a rare MSN population marked by Chst9 that exhibits exceptionally high expression of the {micro}OR and is conserved across species. Notably, Chst9-MSNs comprise a specialized indirect pathway striatal neuron subtype that is molecularly and spatially distinct from canonical striatal populations. Opioids robustly silence Chst9-MSNs, and selective deletion of Oprm1 from this population abolishes fentanyl-conditioned place preference. These findings establish Chst9-MSNs as a critical substrate for opioid reward and define a new cellular framework for therapies targeting opioid use disorder.

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Drake, O. R., Fiore, C. M., Jorgensen, E. T., Newman, C. E., Potter, L. A., Trull, A., Pradeep, A., Ianov, L., Peters, J., Heinsbroek, J. A., Day, J. J.. 2026-07-30. A conserved population of genetically defined striatal neurons gates opioid reward. https://doi.org/10.64898/2026.07.28.741269

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