Unique functional responses differentially map onto genetic subtypes of dopamine neurons

Maite Azcorra; Zachary Gaertner; Connor Davidson; Qianzi He; Hailey Kim; Shivathmihai Nagappan; Cooper K. Hayes; Charu Ramakrishnan; Lief Fenno; Yoon Seok Kim; Karl Deisseroth; Richard Longnecker; Rajeshwar Awatramani; Daniel A. Dombeck

doi:10.1038/s41593-023-01401-9

Unique functional responses differentially map onto genetic subtypes of dopamine neurons

Maite Azcorra, Zachary Gaertner, Connor Davidson, Qianzi He, Hailey Kim, Shivathmihai Nagappan, Cooper K. Hayes, Charu Ramakrishnan, Lief Fenno, Yoon Seok Kim, Karl Deisseroth, Richard Longnecker, Rajeshwar Awatramani^*, Daniel A. Dombeck^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine neuron subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1 ⁺ subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine neuron subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

Original language	English (US)
Pages (from-to)	1762-1774
Number of pages	13
Journal	Nature neuroscience
Volume	26
Issue number	10
DOIs	https://doi.org/10.1038/s41593-023-01401-9
State	Published - Oct 2023

Funding

We thank everyone who provided advice and critiques on this manuscript: T. S. Hnasko, J. B. Issa, Y. Kozorovitskiy, S. Lammel, A. Miri, J. Y. Oh, J. G. Parker, D. J. Surmeier and F. Xuan. We also thank D. Raj for coordination of Aligning Science Across Parkinson’s compliance. This work was funded by Aligning Science Across Parkinson’s (ASAP-020600) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF) (R.A. and D.A.D). For the purpose of open access, the authors have applied a CC BY public copyright license to all Author Accepted Manuscripts arising from this submission. This work was also supported by grants from the National Institutes of Health (R01MH110556, R.A. and D.A.D.; National Institute of Neurological Disorders and Stroke (NINDS) 1R01NS119690-01, R.A.; National Institute on Drug Abuse P50 DA044121-01A1, R.A.; NINDS 1F31NS115524-01A1, Z.G.; National Institute of General Medical Sciences 5T32GM008152-34, Z.G.; National Cancer Institute CA060553, core support; 1S10OD025120, core support; 1S10OD011996-01, equipment and 1S10OD026814-01, equipment) and from La Caixa Fellowship (M.A.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

ASJC Scopus subject areas

General Neuroscience

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Azcorra, M., Gaertner, Z., Davidson, C., He, Q., Kim, H., Nagappan, S., Hayes, C. K., Ramakrishnan, C., Fenno, L., Kim, Y. S., Deisseroth, K., Longnecker, R., Awatramani, R., & Dombeck, D. A. (2023). Unique functional responses differentially map onto genetic subtypes of dopamine neurons. Nature neuroscience, 26(10), 1762-1774. https://doi.org/10.1038/s41593-023-01401-9

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abstract = "Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine neuron subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1 + subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine neuron subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.",

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Unique functional responses differentially map onto genetic subtypes of dopamine neurons

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