Cortical and Thalamic Afferent Connectomes Distinguish ACC Subregions of the Macaque Brain

In humans and nonhuman primates, the anterior cingulate cortex (ACC) is an interface between "interoceptive" and "exteroceptive" domains. The ACC contains discrete subdivisions that are distinct in cytoarchitecture, connectivity, and function. The subgenual ACC (sgACC) is a key area for arousal state modulation. Importantly, the sgACC is dysregulated in major depression and a target for neuromodulation therapies, including deep brain stimulation. In contrast, the perigenual ACC (pgACC) is important for cognitive functions, including social decision-making. Understanding the major sources of afferent input to the sgACC and pgACC is essential for elucidating functional modulation, including in major depression. We took a mesoscopic, "connectomic" approach to examine the balance of projections to ACC subdivisions from two sources of glutamatergic input: the prefrontal cortex (PFC) and insula and the thalamus (n = 6 macaques). Using retrograde tracer injections into ACC subdivisions in male macaques, and unbiased statistical clustering, we revealed that the ACC subdivisions are under the influence of strikingly different "heavily weighted" (HW) inputs from PFC and thalamus. Only one cortical region, area 10m, has HW projections to both sgACC and pgACC, suggesting an integrative role. Additionally, the pgACC sends "top-down" inputs to the sgACC, without significant "bottom-up" return input. Finally, ACC and thalamus-ACC circuits are hierarchically organized, governed by cortical granularity and thalamo-cortical connectivity. Agranular cortices and their associated thalamic nuclei formed most inputs to the sgACC. In contrast, pgACC receives a balanced set of afferents from agranular, dysgranular, and granular cortices, coupled with inputs from broader thalamic regions associated with these cortices.