Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping

Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors. [Display omitted] •VTA dopamine (DA) and GABA neurons receive similar inputs from diverse sources•VTA-DA neurons projecting to different output sites receive biased input•VTA-DA neurons projecting to lateral and medial NAc innervate non-overlapping targets•A top-down anterior cortex→VTA-DA→lateral NAc circuit is reinforcing A combination of state-of-the-art viral-genetic tools shows that dopaminergic neurons in the ventral tegmental area (VTA-DA) employ biased-input/discrete-output circuit architecture, allowing the construction of an input-output map for further investigation of the neural circuits underlying the different functions of these neurons in psychological processes and brain diseases.