It was recently demonstrated that exposure to novel configurations of objects in familiar environments enhances long-term depression (LTD) in vivo (1). LTD is an important cellular physiological process involved in memory reformulation and memory pathway regeneration. Recently we developed a cognitive training program aiming to impair cognitive decline in pathologies leading to saturation of synaptic function. Rats undergoing this 3-week training were shown to express enhanced LTP evoked by theta-burst stimulation (five or ten 100Hz bursts, 4 stimuli, separated by 200 ms) and depotentiation induced by low frequency stimulation (LFS, 1Hz, 15min) in the CA1 area of hippocampal slices obtained from trained rats. Male Wistar rats (4 weeks-old at the beginning of training) were exposed for two weeks to three objects always presented in a new spatial configuration. Objects were placed inside wholes at the corners of an 80x80cm square arena (holeboard). Exposure either to objects in a fixed configuration or absence of objects were used as control. Behaviour during the training sessions was evaluated by addressing exploratory activity (nose-pokes, rearings and total distance travelled). In the final day of training all animals were exposed to objects in a new configuration. The impact of this training program in hippocampal-dependent spatial learning was evaluated using the radial-arm maze test. The latency to find each of the three baited arms, number of wrong arm entries and re-entries in previously visited baited arms were determined. During training, all animals showed increased exploratory activity and decreased general exploration of objects (nose-pokes). In the final day, the animals exposed to this situation for the first time showed increased general exploration of objects (nose-pokes). Animals that were submitted to the training program (n=9) and matched controls experiencing repeated exposure to objects kept in a fixed configuration (n=9) showed decreased latency to find all baited arms in the radial arm maze when compared to animals trained in the absence of objects (n=9). All these groups performed better in the radial arm maze when compared to animals that were never exposed to the holeboard (n=8). When tested one week after the end of radial arm training, trained rats were more efficient (P<0.05, One-Way ANOVA) in finding the baited arms (radial arm recall test) suggesting that they have better retention of memories. Altogether, this suggests that training routines based on these aspects of novelty exposure may have a significant impact on cognitive performance in spatial learning tasks. This may be useful in cognitive recovery in neurological diseases involving synaptic pathology such as temporal lobe epilepsy.