Widespread origin of the primate mesofrontal dopamine system

The dopaminergic innervation of the frontal cortex, commonly implicated in psychiatric and neurological disorders, has traditionally been associated with a circumscribed midline group of ventral tegmental area (VTA) neurons. We have employed a combination of retrograde tracing, using fluorescent dyes, and tyrosine hydroxylase (TH) immunohistochemistry to amplify knowledge of frontal cortex-projecting dopamine (DA) neurons in non-human primates. Injections of retrograde fluorochromes were made in areas 46, 8B/6M, 12, 4, 24, and the prelimbic (PL) and infralimbic areas (IL) of the rhesus monkey. The mesencephalic distribution of neurons exhibiting both retrograde labeling and TH immunoreactivity or retrograde labeling alone was examined from the level of the mammillary bodies to the locus coeruleus. DA afferents innervating the macaque frontal cortex as a whole originate from an unexpectedly widespread continuum of neurons distributed in the dorsal aspects of all three of the mesencephalic DA cell groups A9, A10 and A8; generally corresponding to the DA cells of the substantia nigra (SN), VTA, and the retrorubral area (RRA) respectively. A large number of these retrogradely labeled neurons are non-dopaminergic. The dorsal frontal cortex (areas 46, BB/6M and 4) receive DA projections primarily from the full medial-lateral extent of A9 cells dorsal to the SN pars compacta (i.e. A9 dorsalis), the RRA and to a lesser extent from the A10 parabrachial pigmented nucleus (PBPG) and linear nuclei, the latter of which have been associated with the mesocortical DA system. In contrast, the ventromedial PL and IL exhibit a significantly more robust input from the PBPG and midline linear VTA nuclei than from the lateral groups. The anterior cingulate cortex (area 24) is innervated by a group of DA neurons primarily located between these laterally and medially concentrated populations. These findings demonstrate a degree of compartmentalization of the mesofrontal DA system in primates, and suggest that this projection should no longer be viewed as a unitary midline system.