Unilateral intrahippocampal injections of tetrodotoxin were used to temporarily inactivate one hippocampus during specific phases of training in an active allothetic place avoidance task. The rat was required to use landmarks in the room to avoid a room-defined sector of a slowly rotating circular arena. The continuous rotation dissociated room cues from arena cues and moved the arena surface through a part of the room in which foot-shock was delivered. The rat had to move away from the shock zone to prevent being transported there by the rotation. Unilateral hippocampal inactivations profoundly impaired acquisition and retrieval of the allothetic place avoidance. Posttraining unilateral hippocampal inactivation also impaired performance in subsequent sessions. This allothetic place avoidance task seems more sensitive to hippocampal disruption than the standard water maze task because the same unilateral hippocampal inactivation does not impair performance of the variable-start, fixed hidden goal task after procedural training. The results suggest that the hippocampus not only encodes allothetic relationships amongst landmarks, it also organizes perceived allothetic stimuli into systems of mutually stable coordinates. The latter function apparently requires greater hippocampal integrity.T he rodent hippocampus is a key neural system for processing information about the current spatial arrangement of stimuli and events (1-4), but it is still unclear what spatial computations the hippocampus actually does. One direction of the current experimental effort in this area is studying what aspects of spatial information the hippocampal network stores (5-12); a second is studying what spatial computations an intact hippocampal system is necessary for (13)(14)(15)(16)(17)(18)(19).It is crucial for this latter approach that there are behavioral paradigms, with clearly defined demands, that subjects must solve by using a limited set of potential solutions. The standard, variable-start, fixed hidden goal place navigation task in the water maze (20) has been invaluable because it allows the optimal solution to be readily distinguished from other less efficient strategies. The optimal strategy is for the rat to learn the allothetic relationships between distant, typically visual stimuli and the position of the escape platform. The absence of stable stimuli on the liquid substrate, like visual and tactile marks and odor cues, and the use of variable start locations make it difficult after standard training for the rat to solve the task optimally by using beacon-guided, praxis, or route-following strategies.Since the early eighties, place learning in the water maze has been used in lesion studies to elucidate the role of the hippocampus in spatial cognition (21,22). Selective bilateral lesions of the dentate gyrus and CA3-CA4 were found to severely impair water maze performance (23). However, in that study, unilateral dentate gyrus lesions, but not CA3-CA4 lesions disturbed water maze performance.One difficulty in interpreting t...

Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of ␤-amyloid (A␤) plaques and neurofibrillary tangles in specific brain regions. Although A␤ derived from the A␤ precursor protein (␤-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and͞or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type ␤-APP751 isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form A␤ deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month-and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal ␤-APP751 transgene-induced memory impairment, which may be caused by ␤-APP overexpression, isoform misexpression, or elevated soluble A␤.