Functional Responses Map onto Genetic Subtypes of Dopamine Neurons

Azcorra, Maite

doi:https://doi.org/10.21985/n2-0j0t-1r50

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Functional Responses Map onto Genetic Subtypes of Dopamine Neurons

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Dopamine neurons are characterized by their response to unexpected rewards, but some also fire during movement and in response to aversive stimuli. Dopamine neuron diversity has also been observed based on their genetic expression profiles, suggesting that different functions might map onto such genetic subtypes. However, this has not been tested.Here, we functionally characterized four previously described genetic subtypes of dopamine neurons in the substantia nigra pars compacta, the Sox6+, Calb1+, Vglut2+, and Aldh1a1+ subtypes, and discover a new subtype, Anxa1+. We first establish that two of these genetic subtypes, Sox6+ and Aldh1a1+, are functionally heterogeneous, which leads us to search for and discover a new sub-population within Sox6+/Aldha1a1+ neurons: the Anxa1+ subtype. We then establish that the Vglut2+, Calb1+ and Anxa1+ subtypes each have a unique set of responses to rewards, aversive stimuli, accelerations and decelerations which are specific to each subtype even when they overlap anatomically. Remarkably, reward responses were not detected in one subtype, Anxa1+, which instead displayed acceleration-correlated signaling. We also show that these signaling patterns are highly-correlated between somas and axons within subtypes, rejecting the possibility that these differences might emerge due to local cholinergic modulation in striatum. Furthermore, we use these same genetic markers to show that different DA subtypes originate from different progenitor pools during development, that they are differentially vulnerable in Parkinson’s disease, and provide evidence to help explain why. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

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