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]. …”

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

“…Corresponding to the tail of the striatum (TS), this domain is densely innervated by excitatory inputs from the entorhinal, auditory and visual cortices and sensory thalamic nuclei including the lateral and medial geniculate thalamus and the ventral posterior nucleus (Gangarossa et al ; Menegas et al ; Hunnicutt et al, ; Jiang and Kim ). The integration of the information arising from these cortical and thalamic areas is modulated by dopaminergic (DA) neurons clustered in the lateral part of the substantia nigra pars compacta (Gangarossa et al ; Menegas et al ; Poulin et al ). These DA neurons, which express VGLUT2 and lack D2 autoreceptors (Gangarossa et al ; Poulin et al ), contribute to reinforcement learning that promotes avoidance of threatening stimuli (Menegas et al ).…”

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 . , ).…”