The time of genesis, embryonic origin and differentiation of the brain stem monoamine neurons in the rhesus monkey.

Neurogenesis of the locus coeruleus (LC), substantia nigra (SN) and raphe nuclei (RN) was analyzed in autoradiograms prepared from postnatal rhesus monkeys that had been exposed to a pulse of [3H]thymidine on selected embryonic (E) days of the 165-day gestational period. Heavily labeled monoamine (MA) neurons were present only in monkeys exposed to the isotope between E27 and E36 with the peak around E30-E33. The majority of neurons generated on E30 eventually become situated in the medial part of the LC, whereas most cells of the lateral portion are generated on E32 and E33, indicating the existence of a mediolateral spatiotemporal gradient. Proliferation of neurons destined for the compact portion of the LC peaks around E32, whereas production of subcoeruleus cells proceeds more evenly throughout the E30-E33 period. SN neurons are generated between E36 and E43, with peak labeling around E38-E40, and no appreciable spatiotemporal gradients. Neurons of the ventral tegmental area are also generated between E38 and E43. Neurogenesis of the RN occurs between E28 and E43 with only a moderate rostrocaudal spatiotemporal gradient. Neurons of raphe dorsalis and centralis superior undergo final mitosis between E28 and E35, with the peak on E30, whereas cells of raphe magnus, pontis, obscurus and pallidus are produced between E35 and E43, with the peak between E38 and E40. In general, MA neurons that project to different targets may be produced simultaneously within each nucleus irrespective of any spatiotemporal gradients. Examination of another series of fetuses sacrificed at various short intervals after exposure to [3H]TdR revealed that all MA neurons arise in the ventricular zone with each MA nucleus being generated at a specific level of the brain stem. Postmitotic MA cells migrate to their final location along specific pathways, and settle in patterns corresponding to the sequence of their genesis. Morphometric analysis indicated that after reaching their final destinations, the somas and nuclei of all MA neurons grow according to the same tempo and sequence irrespective of the developmental schedules of their synaptic targets.