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

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.