Projections of the orbital and medial prefrontal cortex to the ventral tegmental area in the macaque monkey

The orbital and medial prefrontal cortex (OMPFC) in macaque monkeys sends discreet glutamatergic projections to the ventral tegmental area (VTA) (Ongür et al., J Comp Neurol, 1998, 401:480-505; Frankle et al., Neuropsychopharmacol, 2006, 31:1627-36). These projections likely provide a mild direct influence on VTA activity, in addition to a stronger indirect influence involving intermediary glutamatergic diencephalic nuclei. On the basis of its connectivity, OMPFC has been divided into orbital ‘sensory’ (OPFC) and medial ‘visceromotor’ (MPFC) networks (Price, ANYAS, 2007, 1121:54-71). Projections to VTA originate from both networks but whether their density varies across areas within a single network and whether they are topographically organized within VTA remain unknown. Here, we examined (1) the distribution of anterograde labeling produced in VTA with injections of biotin dextran amine or fluororuby in distinct architectonic areas in OPFC and MPFC, and (2) the distribution of retrograde labeling produced in PFC with injections of cholera toxin b or fluorescent dextran in VTA. The analysis of the anterograde labeling confirmed prior evidence that PFC contributes only moderate projections to VTA, in contrast with their projections to other targets (e.g. striatum). The density of anterogradely labeled fibers with varicosities in VTA varied with the location of the injection site, so that each network had areas contributing more projections than others. Injections in the medial network produced overall more labeling than injection in the orbital network. Injections in areas 25, 24b, 32, and the intermediate agranular insula (Iai) produced relatively dense labeling. In contrast, injections in areas 10o, 11m and 14c produced sparse or no labeling. In the orbital network, only injections in area 13b and in the posterior median agranular insula (Iapm) produced relatively dense labeling with no major difference between areas. Injections in all the other areas including areas 13l, 11l, 12m, 12r and 12l produced sparse or no labeling. A comparison of the spatial distribution of the labeled fibers in VTA revealed a considerable overlap of the projections from the different areas with only a subtle trend for medial projections to terminate more lateral and rostral than orbital projections. Retrograde tracers injections in VTA supported the heterogeneity of the areal distribution of the cells of origin of PFC projections to VTA. Large injections preferentially labeled areas from which dense labeling was obtained in VTA. Smaller injections tended to label only a subset of these areas supporting the existence of a discreet internal topography within VTA