Prenatal development of nucleus basalis complex and related fiber systems in man: A histochemical study

Abstract

To provide parameters for study of the “cholinergic” innervation of a human fetal cerebrum, we have analyzed the prenatal development of histochemical reactivity in the nucleus basalis complex (a magnocellular complex known to contain a high concentration of cholinergic perikarya). Brains from fetuses and premature infants ranging between 8 and 35 weeks of gestation were frozen cut and processed by the thiocholine method for the demonstration of acetylcholinesterase activity. Since no consistent results were obtained with inhibitors on the material younger than 15 weeks, the histochemical reactivity for early stages was expressed as the total cholinesterase reactivity. The first sign of histochemical differentiation of the basal telencephalon is the appearance of a dark cholinesterase reactive “spot” situated between the developing lenticular nucleus and basal telencephalon surface as early as 9 weeks of gestation. The first cholinesterase reactive bundle connects this reactive area (nucleus basalis complex anlage) with the strongly reactive fiber system situated along the dorsal side of the optic tract. During the next “stage” (10.5 weeks), there is a significant increase in the size of the nucleus basalis complex and strongly cholinesterase reactive neuropil occupies the sublenticular, diagonal and septal areas. At this stage we have seen two new cholinesterase-reactive bundles: one well developed cholinesterase reactive fiber stratum approaching (but not penetrating) the neocortical anlage through the external capsule and another minute bundle running towards the medial limbic cortex through the precommissural septum. The supraoptic fiber system can be traced now to the pregeniculate area and the tegmentum. At 15 weeks, the first acetylcholinesterase reactive perikarya appear and the nucleus basalis complex anlage becomes segregated into several strongly reactive territories, corresponding in position to the medial septal, diagonal and basal nuclei as defined on adjacent Nissl stained sections. At this stage, fibers from the nucleus basalis complex enter the “white” matter of frontal, temporal, parietal and occipital parts of the cerebral hemisphere via the external capsule. Between 15 and 18 weeks, acetylcholinesterase fibers spread throughout the “white” matter of the cerebral hemisphere. In the next “stage” (18–22 weeks), strongly reactive fibers can be followed from the nucleus basalis below the putamen and through the external capsule to the transient, synapse-rich subplate zone of frontal, temporal, parietal and occipital cortices. Fibers from rostromedial divisions of the nucleus basalis complex extend above the developing corpus callosum and form “limbic” bundles—longitudinal striae and the ventral cingulum or run below the corpus callosum as a part of the ventral fornix. These supracallosal fibers penetrate the dorsal archicortex and reach the subplate zone of the parahippocampal gyrus. In addition, strongly reactive fibers can be traced from the nucleus basalis complex to subcortical structures: the amygdaloid, putamen, caudate and the mediodorsal thalamic nuclei. Between 22 and 30 weeks (preterm infants age) there is a significant increase in the number of large, strongly reactive neuronal perikarya in all divisions of the nucleus basalis complex: rostromedial, intermediate and caudolateral. The most prominent part of the nucleus basalis complex is the nucleus basalis which contains the largest and the most numerous neurons. It can be divided into the small rostromedial part (pars diffusa), the main intermediate part (pars compacta) and the posterior lateral division which consists of numerous (7–10) cell aggregations (pars aggregata), the most rostral corresponding to the nucleus subputaminalis and the most caudal intermingling with the amygdala. Concomitantly, the strong acetylcholinesterase reactivity was observed in the deepest layers and in the marginal zone of the neocortex, parahippocampal gyrus and hippocampal formation. In conclusion, the nucleus basalis complex develops the earliest acetylcholinesterase activity in the telencephalon and sends widely distributed fibers to the anlage of neocortex and limbic cortex by the end of the second trimester of gestation. The development of cortical layer innervation coincides with the appearance of the “adult” pattern of topographical relationships. These results provide new data on the development of the nucleus basalis complex and on the early, prenatal “cholinergic” innervation of cerebral cortex. These findings also suggest developmental interaction of basal forebrain fibers with other cortical afferents and offer a new explanation for the anatomical substrate of regulation of behavioural states in the human preterm infant.