Organization of neuropeptide systems in the human brain

Abstract Neuropeptides are functionally diverse signaling molecules in the brain, regulating a wide range of basal bodily and cognitive processes. Despite their importance, the distribution and function of neuropeptides in the human brain remains underexplored. Here we comprehensively map the organization of human whole-brain neuropeptide receptors across multiple levels of description, including molecular and cellular embedding, mesoscale connectivity and macroscale cognitive specialization. Using gene transcription as a proxy, we reconstruct a topographical cortical and subcortical atlas of 38 neuropeptide receptors across 14 different neuropeptide families. We find that most neuropeptide receptors are highly expressed either in the cortex or subcortex, delineating an anatomical cortical–subcortical gradient. Mapping neuropeptide receptors onto hypothalamic nuclei, we demonstrate that neuropeptide receptor gene expression recapitulates fundamental anatomical divisions in the hypothalamus. Neuropeptides preferentially colocalize with metabotropic neurotransmitters, suggesting a system-wide correspondence between slow-acting molecular signaling mechanisms. To investigate the behavioral consequences of distributed neuropeptide systems, we apply meta-analytical decoding to neuropeptide maps and show a spectrum of functions, from sensory-cognitive to reward and bodily functions. Finally, using evolutionary analysis we find extended positive selection for neuropeptides in early mammals, suggesting that refinement of neuropeptides coincides with the emergence of neocortex and higher cognitive function. Collectively, these results show that neuropeptide receptors are highly organized across the human brain and closely intertwined with multiple features of brain structure and function.