The natural axis of transmitter receptor distribution in the human cerebral cortex

Significance

Communication between cells in the brain relies on different types of transmitter receptors. Can we uncover organizational principles that harness the diversity of such signatures across the brain? We focus on the human cerebral cortex and demonstrate that the distribution of receptors forms a natural axis that stretches from association to sensory areas. Moreover, traversing this axis entails changes in the diversity, excitability, and mirrored density that reflect a basic division in receptor types, that is, ionotropic and metabotropic receptors. The unraveled principles offer explanatory depth for diverse phenomena and entail concrete, testable predictions.

Abstract

Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density); excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density); and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.