Cross-species neural co-culture uncovers metabolic signatures of cellular crosstalk

Primates are distinguished by large brains relative to body size, with humans showing the greatest expansion. This increase in brain size evolved alongside advanced cognitive abilities as well as an elevated energetic demand. Importantly, allometric scaling alone does not explain this increased metabolic requirement, suggesting that other cellular mechanisms may be driving the unique energetic capacity of the human brain. Brain metabolism is critical for neurological function by providing the energy necessary for neuron firing. Much of metabolism in the brain is carried out by astrocytes: a type of glial cell that have long been viewed as passive support cells for neurons. More recent research has highlighted the unique roles of astrocytes in many critical neurological processes; however, it is less understood how astrocytes differ among species. To better characterize this, we developed a cross-species co-culture model of astrocytes and neurons from human or chimpanzee-derived iPSCs. This co-culture system allowed us to assess cell-type specific effects as well as species-specific differences in cellular interactions that may be driving overall differences in brain metabolism. We conducted single-cell RNA-sequencing as well as Seahorse XF Mitochondrial Stress tests and observed that human neural co-cultures are more metabolically active than chimpanzee neural co-cultures. Cross-species co-culture systems also highlight that astrocytes are driving major species differences in metabolism, whereas neurons are highly responsive to astrocytic activity. We conclude that both neurons and astrocytes have evolved differently across primates, and that metabolic interactions between these cell types are key contributors in primate brain evolution.