The impact of past history on learning and memory across the lifespan is complex and largely unknown. In particular, a previous learning experience may be crucial in individuals with mild cognitive deficit, and the nature of that experience might influence whether that deficit is amplified or abrogated. Experience is likely relevant whether the deficit is due to a genetic problem, environmental insult, or aging. Here we explore the effect of a past learning experience on subsequent performance in a mouse genetic model known to cause impairment in learning and memory. The behavioral testing paradigm described can be useful in a number of other situations where cognitive impairment is present. Learning theory states that prior training on an easy discrimination task facilitates learning of a difficult discrimination task more than the equivalent amount of training on the difficult discrimination task alone (Lawrence 1952). This phenomenon, called easy-hard learning, or transfer along a continuum, is well known in the experimental literature on animal learning (Lawrence 1952; Riley 1968). One factor in easy-hard learning is stimulus generalization (Gluck and Myers 1993). After learning, generalization of learned responses to nearby stimuli might account for some of the facilitation of learning. More recent studies in rodents have also shown that prior learning experience facilitates performance when the same task is subsequently tested (Dellu et al. 1997; Vicens et al. 1999, 2002; Markowska and Savonenko 2002). In contrast, the effects of exposure to a hard-learning task followed by an easy-learning task are largely unreported. If the hard task is learned, then through stimulus generalization, the subsequent easier task will likely be learned very quickly. However, if the hard task is not learned, stimulus generalization would not occur and the subsequent easier task may not be learned. Would this lack of success be neutral or would it negatively impact future learning? We hypothesized that previous exposure to stimuli that do not become associated with successful learning may, in fact, hinder learning in a subsequent easier task. This would result from a phenomenon termed latent inhibition, which occurs when the pre-exposed stimuli have lost associability or salience (Chamizo 2003). Such initial unreinforced stimulus exposure (e.g., unsuccessful learning) may impair learning of a new task because an animal must now respond to features it previously was unable to use successfully. However, the negative impact of a failed experience may not be evident under all conditions and more sensitive models may be needed to uncover it. The studies on learning transfer were conducted in intact animals, and little is known about the role of past experience with either a hard or an easy task in animals that are cognitively impaired. We hypothesized that under conditions of cognitive impairment, the role of prior experience may be more pronounced. Thus, we sought to use an animal model of genetic vulnerability to cognitive impairment to examine the effect of previous success or failure on learning and memory performance. One prominent molecule involved in learning and memory is the cAMP-response element-binding protein (CREB). CREB activates transcription of genes required for long-term synaptic changes involved in memory formation (Dash et al. 1990; Bourtchuladze et al. 1994; Yin et al. 1994; Guzowski and McGaugh 1997). Mice with a targeted disruption of the α and δ isoforms of the CREB gene (CREBαδ--deficient mice) are impaired in the Morris water maze (MWM), a test of spatial learning and memory (Bourtchuladze et al. 1994) and have an altered ability to code space, as demonstrated by decreased spatial selectivity and stability of hippocampal place cells (Cho et al. 1998). This impairment, however, is not evident under all testing conditions or genetic backgrounds. CREBαδ--deficient mice are impaired when given two trials per day with a 1-min intertrial interval (ITI), but perform normally with spaced training (Kogan et al. 1997). The memory deficit in CREBαδ--deficient mice is, therefore, not absolute. Under highly demanding conditions, the mice are unable to acquire or retain adequate information for learning and memory and are impaired. Under less demanding conditions, the mice are unimpaired. This may be due to related transcription factors (e.g., CREM or the CREB β isoform which is up-regulated; Blendy et al. 1996) and may make up for the deficit. Spatial learning and memory performance of CREBαδ--deficient mice in different genetic backgrounds have been reported to show either a genetically dose-dependent effect (Gass et al. 1998) or no impairment at all (Graves et al. 2002). Further, various CREB mutants (in the 129SvEv × C57BL/6 background) with either a marked reduction or complete loss of hippocampal CREB exhibit only modestly impaired water maze learning (Balschun et al. 2003). Thus, mice with a CREBαδ- mutation on a C57BL/6 × 129SvJ background, that show test-condition-dependent spatial learning and memory, can be considered an animal model of mild cognitive impairment. These mice have a genetic vulnerability to impaired learning and memory that is highly influenced by environmental conditions. Since the learning and memory deficit of CREBαδ--deficient mice is not absolute, we asked whether their performance is determined by the intrinsic difficulty of the task or by other variables (e.g., emotional or psychological). In Experiment 1, we sought to replicate the learning and memory deficit of CREBαδ- homozygous-deficient mice in the two trials per day with a 1-min ITI protocol (Kogan et al. 1997), assess their performance in a protocol different from that already published, which may rescue the deficit, and assess the learning and memory ability of CREBαδ- heterozygous-deficient mice. In Experiment 2, we examined the influence of previous experience on subsequent learning and memory performance by randomly assigning wild-type (WT) and CREBαδ- homozygous-deficient mice to one of two MWM sequence protocols. We asked the following questions: If given success in a learning task, how do CREBαδ--deficient mice then perform in a more demanding task? If impaired in a highly demanding task, how do these mice then perform in a less demanding task?