Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches

Abstract

Midbrain dopamine (DA) neurons have diverse functions that can in part be explained by their heterogeneity. Although molecularly distinct subtypes of DA neurons have been identified by single-cell gene expression profiling, fundamental features such as their projection patterns have not been elucidated. Progress in this regard has been hindered by the lack of genetic tools for studying DA neuron subtypes. Here we develop intersectional genetic labeling strategies, based on combinatorial gene expression, to map the projections of molecularly defined DA neuron subtypes. We reveal distinct genetically defined dopaminergic pathways arising from the substantia nigra pars compacta and from the ventral tegmental area that innervate specific regions of the caudate putamen, nucleus accumbens and amygdala. Together, the genetic toolbox and DA neuron subtype projections presented here constitute a resource that will accelerate the investigation of this clinically significant neurotransmitter system.

The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction

“…Recently, DA neurons from the VTA were shown to project directly to the SCN to resynchronize activity rhythms to photic phase shifting, implying alterations of dopaminergic neurotransmission to NAc may also impact the S N [145]. Further appreciation of subpopulations of midbrain dopaminergic projection neurons may help understand their possible pathway specific involvement in arousal, motivation, and reward [146]. …”

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

“…In the mPFC, there is a mixture of calbindin‐positive DA neurons accompanied by two other distinct neuronal populations (Poulin et al . ). Those findings, in combination with our observations, could potentially open up possibilities for genetically targeted approaches aimed at specific cell populations in the VTA responding to NA.…”

“…Recent advances in genetic tools aimed at dissecting the various populations of DAergic neurons in the VTA have revealed at least several distinct classes distinguishable by conditional genetic tools, with significantly varied patterns of innervation (Poulin et al . , ; Beier et al . ).…”

“…Recently, functional dissection of DA neuronal subpopulations with intersectional genetic tools has revealed further subspecification and diversity of neurons projecting to different areas of the forebrain (Poulin et al . , ).…”

“…Mounting evidence points to differences in ion channel, D 2 autoreceptor, and DA transporter expression in DA neurons forming the mesocortical (VTA to mPFC) and mesolimbic (VTA to striatum and amygdala) circuitry (Juarez and Han 2016). Recently, functional dissection of DA neuronal subpopulations with intersectional genetic tools has revealed further subspecification and diversity of neurons projecting to different areas of the forebrain (Poulin et al 2014(Poulin et al , 2018.…”