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Abstract:
The von Economo (VEN) and fork (FN) neurons are unique neuronal morphotypes found predominantly in the anterior insular and cingulate cortices (AIC and ACC) in primates and in a few other mammals. We previously showed that the VEN, FN and a relatively small group of local pyramidal neurons (PN) project to the periaqueductal gray (PAG) and parabrachial nucleus (PBN), supporting the idea of interoceptive prediction errors mitigation through sensory gating and autonomic control. Prior studies in macaques concluded that AIC and ACC do not project to further caudal brainstem nuclei, hereby limiting their top-down influence. Here, we examined the distribution of axon terminals with injections of anterograde tracers in AIC, as well as the distribution of cortical somata with injections of retrograde tracers in the lateral amygdala (LA), PAG, PBN, locus coeruleus (LC), caudal brainstem solitary (Sol), dorsal motor vagus (DMV) and retroambigus (RAmb) nuclei, and cervical spinal cord (C5-7).
Anterograde labeling occurred in all the diencephalic, midbrain and brainstem nuclei. Sparse labeling occurred in the corticospinal pyramidal tract and in lamina 1 in the 1st cervical segment. Retrograde labeling of all three neuronal morphotypes occurred in layer 5 of AIC and ACC with injections in LA, PAG, PBN, and lower brainstem, but not in C5-7. The ratio of retrogradely labeled VENs over the total number of labeled neurons in layer 5 in AIC was significantly higher (PBN, 28%; PAG, 17%; LA, 21-26.3%; LC, 13.3%; Sol/RAmb, 10.8%) than the overall VEN population number in adjacent Nissl-stained sections (3%). To further investigate the corticospinal projections, we examined the labeling produced with injections of retrograde tracers in C5-7 in adults vs prenatal E95 and E105 macaques. VEN, FN, and PN were labeled in AIC at E95 and E105 (E95 more than E105) but not in adults.
This study shows that VEN and FN belong to a population of projecting neurons that can potentially influence a much broader set of subcortical regions than previously assumed. Most, if not all, brain regions involved in interoceptive integration and autonomic regulation receive AIC and ACC projections. The added functional value of the VEN and FN to these projections could hypothetically resemble that of the Betz cells in motor control. The corticospinal projections require further investigation, with longer post-injection survival and more caudal injection sites, to test whether only specific spinal segments receive VEN projections (e.g., sympathetic thoracolumbar columns) or whether all corticospinal projections are indeed pruned during development. The latter would constitute a remarkable finding.
