Anterograde and retrograde examination of prefronto-insular connections in the macaque monkey

A recent cyto- and myelo-architectonic analysis demonstrated that the classical agranular, dysgranular and granular ‘sectors’ of the insular cortex in the macaque monkey are divided into consistent and sharply demarcated areas, most of which contain smaller subdivisions or modules (Evrard et al., J Comp Neurol, 2014, 522:64-97). This refined architectonic map readily suggests the existence of a matching modular organization of the connections and functions of the insula. Prior injections of anterograde or retrograde tracers in distinct areas of the orbital and medial ‘networks’ of the prefrontal cortex (OPFC and MPFC) in the macaque monkey labeled small discontinuous ‘patches’ of neurons (Saleem et al., J Comp Neurol, 2008, 506:659-93). In light of the new architectonic map, each of these patches could correspond to a distinct architectonic module. Here, we examined the modular distribution of neurons and axon terminals labeled in the insula with injections of anterograde and retrograde tracers in the distinct OPFC and MPFC network areas. Injections in OPFC areas labeled conspicuous patches of neurons or terminals in both agranular and dysgranular areas. The exact spatial location of each patch adequately matched the location of a distinct architectonic module and varied with the location of the injection site in OPFC. For example, injections in area 13m reproducibly labeled the modules ‘3’ and ‘5’ of the dorsal dysgranular area (Idd3 and Idd5) and the module ‘3’ of the mound dysgranular area (Idm3), whereas injections in area 11l labeled Idm2 and Idm3 as well as Idd4 but not Idd3 and Idd5. Similarly, injections in MPFC areas produced sparser labeling that variably involved Idm2, both modules of the ventral dysgranular area (Idv1 and Idv2), the dorsal and ventral posterior agranular areas (Iapd and Iapv), and the fundal agranular area (Ivfa). The present data demonstrate that each architectonic module recently identified in the macaque insula has distinct connections with distinct OPFC and MPFC areas. This supports the view that the fine architecture of the insula provides the basis for a modular integration of interoceptive and prefrontal activities. Together with the insulo-prefrontal connections, the examination of the connections of each insular module with the rest of the cerebral cortex and with subcortical nuclei will provide a significant insight in the functional organization of the primate insular cortex