Unique functional responses differentially map onto genetic subtypes of dopamine neurons

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. Here, we establish that three genetic dopamine subtypes within the substantia nigra pars compacta each have a unique set of responses to rewards, aversive stimuli, accelerations and decelerations, and these signaling patterns are highly-correlated between somas and axons within subtypes. Remarkably, reward responses were not detected in one subtype, which instead displayed acceleration-correlated signaling. 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.

Heterogeneity of mesencephalic dopaminergic neurons: From molecular classifications, electrophysiological properties to functional connectivity

“…Combined the data from previous scRNA‐seq studies, Azcorra M et al. further linked the functional response of DA neurons to their genetic subtypes and identified three different DA neuron subtypes within the SNc based on the expression of Vglut2 , Calb1 and Anxa1 41 . Notably, the Aldh1a1 + Anxa1 + DA neurons, located in the ventral part of vSNc and primarily connecting to the dorsal striatum, play a role in locomotion acceleration but do not exhibit responsiveness to unexpected rewards.…”

“…Both Calb1 + Vglut2 − and Vglut2 + DA neurons are implicated in the modulation locomotion deceleration, but there is a clear signal difference in their timing in relation to decelerations. 41 Undoubtedly, in the future, these classifications will be revised by incorporating ever-moreprecise functional studies and profiling studies. According to in vivo recordings, DA neurons exhibit three primary activity patterns: a hyperpolarized inactive state, an irregular, slow, single-spike firing mode known as tonic discharge, and a rapid burst or "phasic" firing pattern.…”

“…Vglut2 + DA neurons are located mainly in the lateral part of SNc, projecting to the posterior striatum. Both Calb1 + Vglut2 − and Vglut2 + DA neurons are implicated in the modulation locomotion deceleration, but there is a clear signal difference in their timing in relation to decelerations 41 . Undoubtedly, in the future, these classifications will be revised by incorporating ever‐more‐precise functional studies and profiling studies.…”

“…also show significant responses to reward and aversive stimuli 41 . Among them, Vglut2 + DA neurons respond more strongly to aversive stimuli than reward, while Calb1 + DA neurons respond greater to reward than aversive stimulus and are very sensitive to reward size 41 …”

Characterization of Identified Dopaminergic Neurons in the Mouse Forebrain and Midbrain

“…However, evidence for functional heterogeneity started to accumulate in the early 2000s, with the caveat that it largely relied on uncertain methods of DA identification, notably the action potential waveform in current clamp recordings, or the presence of a hyperpolarisation-activated cation current, Ih, in voltage clamp recordings (Margolis et al 2006; Neuhoff et al 2002; Pignatelli et al 2005). The emergence of technologies allowing the generation of mouse lines which target specific cell types confirmed that DA neurons within the SNC, VTA and OB are highly heterogeneous in terms of their developmental profile, gene expression, morphology, electrophysiological properties, and/or connectivity (Roeper 2013; Morales and Margolis 2017; Kosaka, Pignatelli, and Kosaka 2020; Galliano et al 2018; Greene 2006; Tiklová et al 2019; Poulin et al 2018; 2020; Azcorra et al 2023; Brown et al 2009; Lammel et al 2015). Somewhat surprisingly, no study has yet compared the functional heterogeneity of genetically-identified DA neuron electrophysiological properties within VTA, and across the midbrain.…”