An anatomical study of the development of the septo-hippocampal projection in the rat

T. A. Milner, R. Loy, David G Amaral

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The development of the septal projection to the hippocampal formation of the rat was studied in preparations stained for the demonstration of acetylcholinesterase and in experiments utilizing both orthograde and retrograde tracer techniques. Some of the cells in the medial septal nucleus and in the nucleus of the diagonal band are acetylcholinesterase-positive at least 2 days before birth (fetal day 20), and at least some of their fibers, which travel in the supracallosal stria, the fimbria, and the dorsal fornix, are also stained at this time. Within the hippocampal formation, numerous acetylcholinesterase-positive cells are observed in the hilar region of the dentate gyrus, in strata oriens and radiatum of regio inferior of the hippocampus, in the subiculum and in the entorhinal cortex on fetal day 20, but there are few stained fibers in these fields. By postnatal day 3, however, acetylcholinesterase-positive fibers are consistently observed in the rostral dentate gyrus, hippocampus and subiculum. By postnatal day 5, stained fibers are found throughout the rostro-caudal extent of the hippocampal formation and by postnatal day 14 an adult pattern of acetylcholinesterase staining is established. Especially in the adult preparations it is apparent that acetylcholinesterase-positive fibers enter the hippocampal formation by 3 distinct routes: (1) the fimbria, which appears to supply fibers to the entire rostro-caudal extent of the hippocampus and dentate gyrus; (2) the dorsal fornix, which contributes fibers to rostral levels of the subiculum, the regio superior of the hippocampus and the dentate gyrus; and (3) the supracallosal stria, in which fibers travel to mid-rostro-caudal levels of the subiculum and dentate gyrus. Cells of the medial septal nucleus and the nucleus of the diagonal band were retrogradely labeled as early as two days before birth following injections of wheat germ agglutinin-conjugated horseradish peroxidase or the fluorescent dye Fast blue, into the hippocampal formation. At this time the overall distribution of labeled cells within the septal complex appears similar to that seen in the adult. Injections of tritiated amino acids into the septal complex lead to anterograde labeling of the hippocampal formation as early as fetal day 21, the initial stage at which this procedure was attempted. While terminal labeling is diffusely distributed throughout the hippocampal formation during the first 5 postnatal days, by the end of the second postnatal week an increased density of labeling appears both above and below the granule cell layer of the dentate gyrus, within strata radiatum and lucidum of regio inferior of the hippocampus and in the inner and outer plexiform layers of the subiculum. In addition, by postnatal day 14 it is clear that the temporal half of the hippocampal formation receives a substantially greater innervation than the septal half. These studies lead to the conclusions that: (1) fibers originating in the septal complex are present within the hippocampal formation by at least fetal day 20; (2) septal terminals are diffusely distributed initially and segregate to their mature position during the second postnatal week; and (3) the time-course of development of acetylcholinesterase fiber staining within the hippocampal formation parallels the pattern of innervation by the septal nuclei as demonstrated with amino acid autoradiography, though it lags behind the latter by approximately 5 days.

Original languageEnglish (US)
Pages (from-to)343-371
Number of pages29
JournalDevelopmental Brain Research
Issue number2-3
StatePublished - 1983
Externally publishedYes


  • acetylcholinesterase
  • hippocampal development
  • septal nuclei
  • septohippocampal projection

ASJC Scopus subject areas

  • Developmental Biology
  • Developmental Neuroscience


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