In vivo evidence for a hippocampal adrenergic neuronotrophic factor specifically released on septal deafferentation

Denervation of the hippocampal formation in adult rats through lesions of the septohippocampal pathway was found to induce a trophic growth response in intracortical grafts of sympathetic superior cervical ganglia, and to stimulate regeneration of the intrinsic locus coeruleus adrenergic neurons following chemically induced axotomy. The grafted sympathetic adrenergic neurons grew very poorly into the adjacent hippocampus in animals with the septohippocampal pathways intact. A lesion of the ipsilateral fimbria-fornix or of the medial septum-diagonal band area caused a massive stimulation of axonal growth from the transplanted ganglionic neurons into the denervated hippocampus. This increase was more than 100-fold by 1 month after lesion and about 10-fold by 3 months after lesion. Fluorescence histochemistry revealed that the lesion-induced ingrowth occurred primarily into those areas of the dentate gyrus and hippocampus which were denervated of their septal cholinergic afferents. In addition, the septal and fimbria-fornix lesions induced a marked increase in size and noradrenaline fluorescence of the grafted sympathetic neurons, without any clear-cut effects on the numbers of surviving neurons in the graft. This lesion-induced trophic growth response (increases in axonal outgrowth, cell body size and noradrenaline content) was specific for lesions of the septal (probably primarily cholinergic) innervation of the hippocampus. Thus, extensive denervations induced by lesions of the commissural or perforant path afferents, as well as selective lesions of the intrinsic adrenergic afferents from the locus coeruleus, had no clear-cut effects. The intrinsic central adrenergic neurons were also found to be responsive to the lesion-induced growth-stimulating mechanism. Thus, lesions of the fimbria-fornix or the medial septum-diagonal band area had a marked stimulatory effect on the regeneration of the locus coeruleus noradrenergic neurons after selective chemical axotomy (induced by 5,7-dihydroxytryptamine; 5,7-DHT). Thus, the adrenergic reinnervation of the initially denervated hippocampus was significantly accelerated by 3 weeks after the fimbria-fornix or septal lesions, and the increase persisted for at least 8-10 months after transplantation. These results provide evidence for an adrenergic neuronotrophic factor whose production in the hippocampus normally is under the control of non-adrenergic (probably cholinergic) afferents originating in the septal-diagonal band area. The actions of this putative factor on sympathetic adrenergic neurons resemble those induced by nerve growth factor (NGF). Interestingly, however, the results obtained after 5,7-DHT-induced axotomy indicate that central and peripheral adrenergic neurons are equally responsive, and thus that the putative central adrenergic neuronotrophic factor may play a normal physiological role in the regulation of axonal growth and regeneration within the central nervous system.