SUBCORTICAL PROJECTIONS OF THE VON ECONOMO AND FORK NEURONS IN MACAQUES

Von Economo neurons (VENs) are large, spindle-shaped projection neurons occurring in the anterior insular cortex (AIC) and anterior cingulate cortex (ACC) of primates. Linked to integration of interoceptive, emotional, and autonomic activities, they are selectively vulnerable in neuropsychiatric and neurodegenerative disorders. Prior works hypothesized that the VENs and FNs project primarily to several interoceptive and autonomic brainstem nuclei. Here, we used molecular tracing to test this hypothesis. Anterograde tracer injections in AIC labeled axon terminals in the amygdala, hypothalamus, septum, midline thalamus, periaqueductal gray (PAG), parabrachial nucleus (PBN), locus coeruleus (LC), solitary tract nucleus (Sol) and to a much lesser extent dorsal motor nucleus of the vagus nerve and Ambiguus nucleus. Retrograde tracer injections in the amygdala, PAG, PBN, LC and Sol/10N labeled layer 5 AIC neurons, with an increased contribution of VENs and FNs relative to their overall abundance. Notably, retrograde tracer cases targeting the amygdala revealed an additional cluster of large, spindle-shaped neurons in the entorhinal cortex. Together, these results establish VENs as a specialized subclass of long-range projection neurons embedded within descending interoceptive and autonomic control circuits, indicating a selective engagement of VENs in corticofugal pathways linking cortex to limbic and autonomic effectors, in line with models of interoceptive predictive coding. In addition, the identification of a clustered population of VEN-like neurons in the entorhinal cortex following amygdala injections suggests that VEN-related morphotypes may participate more broadly in limbic networks than previously hypothesized. - Funding: Shanghai MSTPMP 2019SHZDZX02, NSFC Mianshang 32271049, Shanghai Super Postdoc 2024656.