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bioRxiv · 10.64898/2026.03.03.709300

Cortical and thalamic afferent connectomes distinguish ACC subregions of the macaque brain

Myers, D. C.·Love, T. M.·Fudge, J. L.
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Abstract

In human and nonhuman primates, the anterior cingulate cortex (ACC) is an interface between the "interoceptive" and "exteroceptive" domains. The ACC contains discrete subdivisions that are distinct in cytoarchitecture and connectivity, and also serve unique functional roles. The subgenual ACC (sgACC) is a key area for arousal state modulation and processing negative emotion. Importantly, the sgACC is dysregulated in major depression and a major target for neuromodulation therapies such as deep brain stimulation. In contrast, the perigenual ACC (pgACC) is important for a host of cognitive functions, including error monitoring and social decision-making. Thus, understanding the major sources of afferent input to the sgACC and pgACC is essential for elucidating functional modulation, including in major depression and other related disorders. We took a mesoscopic connectomic approach to examine the balance of projections to sgACC and pgACC from two sources of glutamatergic input: the prefrontal cortex (PFC) and insula, and the thalamus (n=6 macaque monkeys). Using paired injections of retrograde tracers into the sgACC and pgACC and unbiased statistical clustering, we revealed that the ACC subdivisions are under the influence of vastly different cortical and thalamic drivers, i.e. heavily weighted inputs. We also found hierarchical rules (governed by cortical granularity and thalamo-cortical connectivity) by which PFC-ACC and thalamus-ACC circuits are organized. Overall, agranular PFC/insula cortices and associated thalamic nuclei are heavily weighted towards the sgACC, whereas pgACC receives a more even balance of afferents from agranular, dysgranular, and granular cortices and the thalamic nuclei with which they are associated. SIGNIFICANCE STATEMENTThe ACC contains discrete subdivisions based on cytoarchitecture and connectivity, which serve unique functional roles. The sgACC and pgACC subdivisions receive many similar inputs based on neuroimaging work. Here, we leverage higher resolution retrograde tract-tracing in macaques to examine the relative weights and relationships of multiple cortical and thalamic afferents to each region. Using unbiased analyses of labeled cells, we conclude that the balance of afferent inputs shifts from a connectome dominated by agranular cortices and their thalamic partners in sgACC, to a more balanced afferent connectome in pgACC, represented by agranular, dysgranular, and granular cortices and their broader thalamic partners. These results facilitate interpretation of functional studies, and bridge understanding of the connectional basis of psychiatric disorders.

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Myers, D. C., Love, T. M., Fudge, J. L.. 2026-03-05. Cortical and thalamic afferent connectomes distinguish ACC subregions of the macaque brain. https://doi.org/10.64898/2026.03.03.709300

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