Sprouting of central noradrenergic fibers in the dentate gyrus following combined lesions of its entorhinal and septal afferents

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Abstract
Virtually all of the afferents to the hippocampal formation undergo collateral sprouting after removal of adjacent afferent systems. However, the central noradrenergic (NA) afferents, which demonstrate a remarkable propensity for regeneration and sprouting in other regions of the brain, have not been found to sprout in the denervated hippocampal formation. The present study was designed to determine if the pattern of innervation by NA fibers in the dentate gyrus of adult rats can be altered by interruption of the other major afferents. The innervation pattern of NA fibers was examined in the dentate gyrus 4 weeks after removal of the ipsilateral and/or contralateral entorhinal afferents and/or transection of the fimbria-fornix and supracallosal stria. The noradrenergic identity of the fibers was indicated by immunoreactivity for dopamine beta hydroxylase (DBH) and peripheral sympathetic fibers were demonstrated by immunoreactivity for nerve growth factor receptor (NGFr), which did not stain cholinergic fibers in this application. In control brains, the noradrenergic innervation of the dentate molecular layer was light and uniform across the width of the layer. Transection of the perforant path (ipsilateral entorhinal afferents) or ventral hippocampal commissure (contralateral entorhinal afferents) resultd in a significant increase in innervation density in the outer half of the molecular layer, and the combination of these two lesions produced the greatest increase. In those brains with transection of the ipsilateral and contralateral entorhinal afferents, the denervated dentate gyrus had a nearly twofold increase in density of DBH-immunoreactive fibers within the outer half of the molecular layer. These fibers tended to course parallel to the pial surface rather that perpendicular as in control sections. Transection of the fimbria-fornix alone had no affect on the innervation pattern of DBH-ir fibers in the molecular layer. When the fimbria-fornix was transected in combination with both of the other lesions, an overall increase in innervation density occurred, but there was no further increase in the difference between the inner and outer halves of the molecular layer. No NGFr-immunoreactive fibers were observed in the molecular layer in any of the brains, indicating that the DBH-immunoreactive fibers in this region were not of peripheral origin. It is concluded that removal of the ipsi- and contralateral entorhinal afferents to the dentate gyrus results in the sprouting of central NA fibers in the outer half of the molecular layer.

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