Time-dependent effects of intrahippocampal grafts in rats with fimbria-fornix lesions

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Abstract
Based on three experiments, this study examined whether behavioral and histological effects of fetal septal or hippocampal grafts placed in the denervated hippocampus depend on the duration of post-grafting delays. Each experiment included four groups of rats: sham-operated rats (Sham), rats with aspirative lesions of the fimbria-fornix (Fifo) and rats given both Fifo lesions and intrahippocampal fetal suspension grafts of either septal (Fifo.ST) or hippocampal (Fifo.HT) origin. All rats were tested (i) for home cage activity, (ii) for activity and reactivity in an open field and (iii) for learning ability in a 8-arm radial maze. Except for home cage activity which was also monitored preoperatively, behavioral tests were conducted between 1–2 months postgrafting in Experiment 1 (EXP1), 5–6 months post-grafting in Experiment 2 (EXP2) and 10–11 months postgrafting in Experiment 3 (EXP3). Each test period lasted 3 weeks. Histological controls consisted of acetylcholinesterase (AChE) and cresyl violet staining. Graft size was estimated by computerized image analysis. Normal rats performed well in each experiment. In all experiments, rats with fimbria-fornix lesions showed increased activity in both their familiar (home cage) and unfamiliar (open field) environments, and their performances in the radial maze task were impaired. In no experiment did grafts, whether hippocampal or septal, affect “noncognitive” behavioral variables. However, maze performance was improved by hippocampal grafts in EXP1 (short delay) and by septal grafts in EXP2 (intermediate delay). No graft-induced effect was found in EXP3 (long delay). Concerning AChE-positivity in the dorsal hippocampus, fimbria-fornix lesions reduced staining densities by at least 60%. Both types of grafts were undiscernably AChE-positive, but only septal grafts provided the denervated hippocampus with a significant AChE-positive fiber ingrowth. Differences among groups in density of hippocampal AChE staining were comparable in all three experiments and no correlation between hippocampal AChE-positivity and maze performance was found. Our results suggest that graft-induced recovery from behavioral effects of fimbria-fornix lesions may depend on both the type of tissue implanted (hippocampal vs septal) and the post-grafting delay (1–2, 5–6 and 10–11 months). The recovery observed at a short post-grafting delay with hippocampal grafts and at a longer post-grafting delay with septal grafts was not persistent and concerned only cognitive function as assessed by radial maze performance. Regarding (i) the absence of any correlation between AChE staining and radial maze performance, and (ii) the lack of graft-derived AChE-positive fiber ingrowth in Fifo.HT rats with improved radial maze performance in EXP1, our results also suggest that factors other than graft-derived cholinergic fiber ingrowth might be involved in the graft-induced recovery observed in the radial maze.