An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields.

The ontogeny of the serotonergic axonal projections may be divided into three periods: one of initial axon elongation (E12-E16), the development of selective pathways (E15-E19) and terminal field development (E19-E21). All serotonergic axons that enter the prosencephalon ascend in the medial forebrain bundle From this bundle fascicles of immunoreactive axons enter several well-defined fiber tracts: specifically, the fasciculus retroflexus, stria medullaris, external capsule, fornix, and supracallosal stria. Axons from these pathways form terminal arborizations in the thalamus, hypothalamus, basal and limbic forebrain, and cerebral cortex. Serotonergic axons appear to be guided by pre-existing non-serotonergic tracts in reaching targets in the forebrain. Innervation of the cerebral cortex is a prolonged process extending from E19 through PND21. Axons enter directly into the marginal and intermediate zones of the immature cortex, at the medial, frontal and lateral edges of the hemisphere, and subsequently spread tangentially to cover the hemispheres. Terminal ramifications then arise from the bilaminar axons and fill in the middle cortical layers. This growth pattern gives rise to tangential and radial gradients in innervation density. While the growth of serotonin axons across the forebrain appears to be a continuous, sequential process, the development of terminal innervation is highly heterogeneous, occurring at different times and at different rates from region to region. Serotonergic axons do not innervate immature, primarily proliferative neuronal populations. The delay in serotonin innervation of the suprachiasmatic nucleus, striatum, and middle cortical layers long after the axons have reached these structures suggests that the formation of serotonin axon terminals is dependent on maturation of other elements in local neuronal circuitry.