Maturing Rat Adrenal Medulla: 3D Organization and the ‘Access Points’ Hypothesis for Opposite Distribution Gradients of A‐ and NA ‐Cells

The mature rat adrenal medulla is characterized by a pronounced asymmetry in the 3D organization of chromaffin tissue as a whole and by oppositely directed gradients in the distribution of adrenaline‐storing (A‐) and noradrenaline‐storing (NA‐) cells. The aim of this study was to characterize the 3D organization of the rat maturing adrenal medulla. Adrenal glands from 1‐ to 2‐week‐old Wistar rats were processed using a highly specific chromaffin reaction according to Honoré, which allows differentiation between A‐ and NA‐cells. A 3D reconstruction of the adrenal medulla was obtained from complete sets of serial sections after A‐ and NA‐cells, blood vessels, nerve fibres, neurons and stroma had been marked on each section. By the time of final differentiation of A‐ and NA‐cells (end of the first postnatal week), the two‐level asymmetry of chromaffin tissue characteristic of the mature adrenal medulla and its close association with bundles of nerve fibres was already clearly evident. At the craniomedial margin, where the main nerve bundles enter the medulla, chromaffin tissue formed cones and cords composed almost exclusively of A‐cells, whereas towards the caudolateral margin A‐cell density decreased and NA‐cell density increased. Integrating these data with published information on embryonic migration of sympathoadrenal precursors and on the development of adrenal medullary innervation and vascularization, we propose the ‘access points’ hypothesis. It proposes that opposite A‐ and NA‐cell gradients result from asynchronous arrest of migrating groups of A‐ and NA‐cell precursors (chromaffinoblasts) as they reach discrete microdomains that provide access to nerve terminals and microvasculature (‘access points’), with earlier‐settling A‐blasts accumulating near the nerve entry zone and later‐settling NA‐blasts occupying remaining access points.