Translational Insights from Cell-type variation across Amygdala Subnuclei in Rhesus Monkeys and Humans

Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, our limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions. Here, we use single-nucleus RNA-sequencing from multiple amygdala subnuclei in both humans (n=3, Male) and rhesus macaques (n=3, Male) to begin to bridge the gap between preclinical rodent models and human disorders. Our results reveal substantial heterogeneity between regions, even when restricted to inhibitory or excitatory neurons. Consistent with prior work, our data highlight the complexities of individual marker genes for uniquely targeting specific cell-types. Cross-species analyses suggest the rhesus monkey model to be well-suited to understanding the human amygdala, but also identify limitations. For example, we identified a cell-cluster in the ventral lateral nucleus (vLA) of the amygdala that is enriched in humans, relative to rhesus macaques. Additionally, we identify specific cell-clusters with relative enrichment of disorder-related genes. These analyses point to the human-enriched vLa cell-cluster as relevant to ASD, potentially highlighting a vulnerability to neurodevelopmental disorders that has emerged in recent primate evolution. Further, we identified a cluster of cells expressing markers for intercalated cells (ITCs) that is enriched for genes reported in human genome-wide association studies of neuroticism, anxiety disorders, and depressive disorders. Together, these data shed light on the composition of the amygdala and identify specific cell-types that can be prioritized in basic science research to better understand human psychopathology and guide the development of potential treatments