An energy costly architecture of neuromodulators for human brain evolution and cognition

Humans spend more energy on the brain than any other species. However, the high energy demand cannot be fully explained by brain size scaling alone. We hypothesized that energy-demanding signaling strategies may have contributed to human cognitive development. We measured the energy distribution along signaling pathways using multimodal brain imaging and found that evolutionarily novel connections have up to 67% higher energetic costs of signaling than sensory-motor pathways. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an upregulation of signaling at G-protein coupled receptors in energy-demanding regions. We found that neuromodulators are predominantly involved in complex cognition such as reading or memory processing. Our study suggests that the upregulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.