Behavioral effects of basal forebrain grafts after dorsal septo-hippocampal pathway lesions

There are many reports that basal forebrain grafts ameliorate behavioral impairments produced by dorsal septo-hippocampal pathway lesions, but several studies have either found that this recovery may be unrelated to concomitant restitution of cholinergic markers, may be modest and depend on certain experimental conditions or instead that grafts may actually exacerbate lesion-induced impairments. In this study, rats received one of three lesions of the dorsal septo-hippocampal pathways or a sham lesion, at 32 days of age, and intrahippocampal basal forebrain grafts or the vehicle control 10 days later. In grafted rats with total aspirative lesion of the fimbria-fornix, there was a substantial AChE-positive hippocampal reinnervation but no improvement of the severe lesion-induced spatial learning deficits, either reference memory or working memory, whether tested at 1 or 5 months post-grafting. In rats with bilateral medial fimbria lesions, grafts were successful, normal in appearance and produced substantial hippocampal cholinergic reinnervation; relative to non-grafted counterparts, however, grafted medial fimbria rats showed an early reference memory impairment and a persistent exacerbation of a working memory deficit. Exacerbation of learning impairments was also apparent in grafted rats with partial hippocampal denervation due to lesion of the cingulate and adjacent cortex above the fimbria-fornix. Nonetheless, basal forebrain grafts normalised general activity in these lesion groups, irrespective of whether the lesion-induced change was an increase or a decrease relative to controls. Graft-derived lesion groups, irrespective of whether the lesion-induced change was an increase or a decrease relative to controls. Graft-derived AChE-positive innervation was more marked than expected in both grafted cingulate-lesioned rats and grafted sham-lesioned rats, while control grafts of fetal cortex (above the septum) produced little or no AChE-positive innervation. Size of basal forebrain grafts, originally 3 microliters at two dorsal sites per hippocampus, increased markedly from rostral to caudal dorsal hippocampus in all groups but did not differ significantly across grafted groups, even with respect to non-lesioned rats. This study adds further evidence that basal forebrain grafts, successful with respect to cholinergic reinnervation, do not always enhance cognitive functions in rat hippocampal lesion models, and confirms that these grafts may have adverse effects after partial septo-hippocampal system lesions. It is important to attend to both the potential negative and positive effects of neural grafts.