The development of the medullary serotonergic system in early human life

The serotonergic (5-HT) neurons of the medulla oblongata are postulated to comprise a system that modulates homeostatic function in response to metabolic imbalances in the internal milieu in a state-dependent manner. In this study, we define the baseline development of the topography of the human medullary 5-HT system in 30 cases ranging from the embryonic period through infancy. We used immunocytochemical techniques with the PH8 antibody which recognizes the key 5-HT synthetic enzyme, tryptophan hydroxylase, and computer-based methods of cell quantitation. In the infant medulla, 5-HT neurons were distributed in raphé, extra-raphé, and ventral positions that place these neurons adjacent to, or intermingled with, the neurons in the lower cranial nerve nuclei and reticular formation that directly mediate respiration, upper airway reflexes, and autonomic function. Along the ventral and ventrolateral surface, 5-HT neurons formed two lateral and one midline "columns" in the rostrocaudal axis that are homologous in position to chemosensitive 5-HT neurons in rats, and that correspond in part to the classic respiratory chemosensitive fields. Serotonergic neurons comprised a subpopulation of the arcuate nucleus along the ventral surface; their short processes directly abutted the surface, suggesting a role for them in monitoring carbon dioxide levels in the cerebrospinal fluid. The medullary 5-HT system began to form in the embryo, with the raphé primordia appearing as early as 7 weeks (the earliest time-point available). By 10-12 weeks, the lateral tegmental 5-HT neurons clustered into the early primordia of extra-raphé subnuclei. By 20 weeks, the "adult-like" topography of the medullary 5-HT system was in place, with subtle (quantitative) changes occurring thereafter. Thus, protracted changes occur from the prenatal period through infancy. These data provide a foundation for 5-HT neuronal analysis in pediatric brainstem disorders, as proposed in the sudden infant death syndrome.