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Abstract

The large spindle-shaped von Economo neuron (VEN) occurs in a specific architectonic area (‘VEN-area’) in the macaque anterior insula (Evrard et al., Neuron, 2012, 74:482-9). Given its relatively large size and localization in layer 5a, the VEN likely projects to distant brain regions including the midbrain periaqueductal gray (PAG) and the parabrachial nucleus (PBN). PBN and PAG have a crucial role in gating interoceptive afferents, and in patterning physiological and behavioral emotional responses. We examined the distribution of neurons retrogradely labeled in the insula with injections of cholera toxin b, fast blue or fluorescent dextran in different columns of PAG or in PBN. Injections in PAG invariably labeled small, discontinuous patches of neurons in the ventral portion of the insula as well as in the medial prefrontal cortex. Using a refined architectonic map of the insula (Evrard et al., J Comp Neurol, 2014, 522:64–97), we observed that the areal affiliation of these patches consistently varied with the location of the injection. Injections in the dorsal lateral column of PAG (dlPAG) sparsely labeled distinct areas posterior to the limen, and densely labeled the intermediate agranular area (Iai), anterior to the limen. Injections in the lateral column of PAG (lPAG) labeled the ‘mound’ dysgranular area (Idm) and the dorsal posterior agranular area (Iapd), posterior to the limen, and the lateral agranular insula (Ial), anterior to the limen. Injections in the ventrolateral column of PAG (vlPAG) labeled both Iai and Ial. In stark contrast with injections in PAG, injections in PBN labeled almost exclusively the very anterior insular areas including Iai and Ial. The rest of the insula and the medial prefrontal cortex lacked labeling. VENs and fork cells were located almost exclusively in Ial and were retrogradely labeled from injections in lPAG, vlPAG, and PBN. The projection of directly adjacent insular areas to different columns of PAG may provide a unique insight in the cortical control of the autonomous system. The selective projection to PBN substantiates our prior evidence for a functional link between PBN and the VEN area in coma (Fischer et al., Neurology, 2016, 90:143-51). In this context, the VEN and their companion FC could have a direct and rapid influence on the autonomic substrate of emotional behavior and conscious awareness of feelings.