Hippocampal lesions can disrupt the acquisition of new memories and tend to increase motor activity. Although hyperactivity may affect exploration, it is unclear how these performance variables contribute to the learning deficit and it is also not known which brain structures are involved. The present study provides evidence for a dissociation between activity and memo?. Following unilateral or bilateral electrolytic lesions of the hippocampus in neonatal rats, we assessed open field behavior and performance of discrete trials alternation in a T-maze. When tested 6 and 20 weeks postoperatively, rats subjected to bilateral lesions were hyperactive. Their performance in the discrete trials alternation task was impaired. In contrast, rats subjected to unilateral lesions did not display an increase in motor activity, but were still deficient in performance on the T-maze. To define whether these behavioral changes were accompanied by secondary changes in structures that project to the hippocampus, we studied the function of the septum and locus coeruleus after the lesions. Septal choline acetyltrans-ferase (CAT, the acetylcholine-synthesizing enzyme) activity was reduced and tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis) activity in noradrenergic lc neurons was increased after both the unilateral and bilateral lesion. Therefore, these changes may contribute to the memory impairment but are not necessarily related to motor hyperactivity. We conclude that a deficit in spatial memory is not attributable to altered performance variables such as activity. Furthermore, spatial memory deficits in both the unilateral and bilateral lesion paradigms may be associated with changes in septal and lc function.