Divergent Whole Brain Projections from the Ventral Midbrain in Macaques

To understand the connectome of the axonal arborizations of dopaminergic midbrain neurons, we investigated the anterograde spread of highly sensitive viral tracers injected into the ventral tegmental area (VTA) and adjacent areas in 3 macaques. In 2 monkeys, injections were centered on the lateral VTA with some spread into the substantia nigra, while in one animal the injection targeted the medial VTA with partial spread into the ventro-medial thalamus. Double-labeling with antibodies against transduced fluorescent proteins (FPs) and tyrosine hydroxylase indicated that substantial portions of transduced midbrain neurons were dopaminergic. Interestingly, cortical terminals were found either homogeneously in molecular layer I, or more heterogeneously, sometimes forming patches, in the deeper laminae II-VI. In the animals with injections in lateral VTA, terminals were most dense in somatomotor cortex and the striatum. In contrast, when the medial VTA was transduced, dense terminals were found in dorsal prefrontal and temporal cortices, while projections to striatum were sparse. In all monkeys, orbitofrontal and occipito-parietal cortex received strong and weak innervation, respectively. Thus, the dopaminergic ventral midbrain sends heterogeneous projections throughout the brain. Furthermore, our results suggest the existence of subgroups in meso-dopaminergic neurons depending on their location in the primate ventral midbrain.