Axonal regeneration and limited functional recovery following hippocampal deafferentation

Although central neurons do not naturally recover following injury, damaged adult septal neurons can regenerate when nerve growth factor (NGF) is provided along with a suitable cellular substrate. This study investigates the outgrowth of axotomized septal neurons grafted with primary fibroblasts genetically modified to produce NGF. Confocal microscope images of double staining for neuritic markers (neurofilament or low-affinity NGF receptor) and the astrocytic marker glial fibrillary acidic protein (GFAP) demonstrated that regenerating neurites crossed dense buildups of astrocytic processes at the edges of NGF-producing grafts and were in apposition with astrocytic processes within NGF-producing grafts. Immunoreactivity for acetylcholinesterase and low-(p75) and high-affinity (TrkA) NGF receptors was dense in NGF-producing grafts but absent in control grafts. NGF-grafted rats exhibited significantly increased hippocampal density of p75-immunoreactive fibers and significantly decreased ectopic hippocampal sympathetic ingrowth as compared to control-grafted rats. Rats with unilateral fimbria-fornix lesions and NGF-producing grafts exhibited ameliorated performance on a simple memory task. These findings demonstrate that implantation of NGF-producing grafts to the lesion cavity allows axotomized septal cholinergic neurons to reinnervate the hippocampus, and that rats receiving these grafts show a partial recovery of function.