Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervation of the cerebral cortex.

The cathecholaminergic (CA) systems have been described as appearing early in the development of the mammalian central nervous system (CNS), but their exact distribution in humans has been studied only following gestational week (g.w.) 13. Furthermore, it is not known when CA fibers initially penetrate the developing cerebral cortex. In this study, the CA cells groups and fibers are described in the human central nervous system from 6 to 13 g.w. as revealed with immunocytochemical techniques, with antibodies raised against three synthetic enzymes of the catecholamine (CA) pathway: tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). At 6 g.w., TH-like immunoreactive (TH-IR) cell groups were widespread through the caudorostral extension of the CNS corresponding to the different dopaminergic mesencephalic and hypothalamic groups. Noradrenergic groups also were labeled in the medulla oblongata and in the locus coeruleus as well as in other areas in the pons. Additional TH-IR cell groups might represent a transient developmental expression of TH similar to that observed in the rat. DBH immunoreactivity labeled primarily the noradrenergic pontic cell groups and, to a lesser extent, groups located in the medulla oblongata. Rare PNMT-IR neurons were detected in the medulla oblongata only at 13 g.w. The main CA bundles described in the adult were also observed in human embryos and fetuses. At 6 g.w., TH-IR pathways extended caudorostrally within the central tegmental tract and the dorsal tegmental bundle, the latter merging with the dopaminergic mesotelencephalic pathway giving rise to the medial forebrain bundle in the basal forebrain. At 7-8 g.w., TH-IR fibers extended to the basal ganglia and the telencephalic wall. The first TH-IR and, to a much lesser extent, DBH-IR fibers penetrated the frontal lateral cortical anlage through the intermediate zone and sparsely through the marginal zone but not through the thin cortical plate. A second stream entered the telencephalic anlage frontomedially, ventral to the septal area. At 11 g.w., numerous TH-IR fibers invaded the subplate layer, but they penetrated the cortical plate only at 13 g.w. At that time, TH-IR and DBH-IR fibers had reached the occipital cortex in a rostrocaudal gradient. The appearance of well-organized CA system already in embryonic stages in humans could be of great importance for normal shaping of the nervous system as well as for development of cortical circuitry.