The pre- and postnatal development of the dopaminergic innervation in the prefrontal cortex (PFC) of the rat is described from embryonic day 14 through postnatal day 90. By embryonic day 15 the dopamine (DA)-containing fibers reach the anlage of the lateral neocortex; 2 days later the first fibers have reached the subplate of the future prefrontal cortex. The process of entering the cortical plate starts just before birth. Prenatally, some dopaminergic fibers can be observed in the marginal zone of both the lateral and the medial wall of the hemisphere. Within 48 hours after birth a large number of dopaminergic fibers can be observed in the marginal zone, i.e., the future layer I, in some subareas of the PFC. A transient appearance of DA-positive fibers is noticed in the late embryonic and early postnatal periods especially in the marginal zone and possibly in the superficial layers of the pregenual cingulate cortex. Changes in the morphology of DA fibers at P4 suggest that the actual DA innervation starts at this age. From postnatal day 6 the different subareas of the PFC can be recognized according to the characteristics of the topographical distribution of the dopaminergic fibers. Until postnatal day 60 the density of the dopaminergic fibers continues to increase. No difference in density and topography was observed between postnatal days 60 and 90.

This paper gives an account of the cytoarchitectonic characteristics that make it possible to delineate, from as early as day 6, different subareas of the prefrontal cortex of the rat. Three phases can be distinguished during postnatal development. The first phase (from day 1 until day 18) is dominated by differentiation of the neurons within the cortical plate and by the formation of the cortical layers. At day 1, regional differences are observed in the cytoarchitecture of the cortical plate which correspond to the future subareas of the prefrontal cortex. The formation of layer IV occurs in the dorsolateral cortex around day 6, and from this age the agranular prefrontal cortex is well demarcated from the other parts of the frontal cortex. Between day 6 and day 10, the cortical plate has disappeared and all cortical layers can be recognized in the prefrontal cortex. Differentiation of the cells within the cortical layers changes the cytoarchitectonic character of the layers through day 18. During the second phase (from day 18 until day 30) little change occurs in the cytoarchitectonic characteristics of the prefrontal subareas. During the third phase (from day 30 until day 90) the delineation of the cortical layers becomes less clear in Nissl-stained sections, and the individual cytoarchitectonic variance increases. On the basis of cytoarchitectonic criteria it can be concluded that the orbital prefrontal cortex develops earlier than does the medial prefrontal cortex.

The present study shows that in the prenatal rat neocortex the GABA immunoreactive neurons are not limited to the marginal, subplate, and intermediate zones, but are also found in all fetal zones of the cerebral anlage. The first GABA-ergic cells are observed on embryonic day 14 in the plexiform primordium. On embryonic day 15, a second population of GABA-ergic cells is observed in the intermediate zone. Beginning on day 16 of gestation and continuing throughout gestation, GABA-ergic neurons are observed in the marginal zone, the subplate zone, the cortical plate, and the ventricular and subventricular zones. Furthermore, while the number of GABA-ergic cells in the cortical plate increases, GABA-ergic neurons in the intermediate zone and subventricular zone decrease in number after embryonic day 19.

The medial and orbital parts of the prefrontal cortex (PFC) increase in volume during the first weeks of postnatal life. At the end of this period, however, the volumes of both parts of the PFC reach a significantly higher value than in adulthood. Subsequently the volumes decrease until the adult volume is attained. The three subareas of the medial PFC (i.e., the medial precentral area, the dorsal anterior cingulate, and the prelimbic area) reach a maximum volume around day 24, while the two orbital PFC subareas (i.e., the dorsal and ventral agranular insular areas) attain their maximum value around day 30. The differences found in the growth pattern of the five PFC subareas, which are innervated by specific subnuclei of the mediodorsal nucleus of the thalamus, suggest a role of these subnuclei in the PFC development.

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