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The triple transgenic Alzheimer’s disease (3xTg-AD) strain is a common mouse model used for studying the pathology and mechanism of Alzheimer’s disease (AD). The 3xTg-AD strain exhibits two hallmarks of AD, amyloid beta (Aβ) and neurofibrillary tangles. Several studies using different gender and age of 3xTg-AD mice to investigate their behavior phenotypes under the influence of various treatments have reported mixed results. Therefore, a comprehensive investigation on the optimal gender, age, and training paradigms used for behavioral studies of 3xTg-AD is necessary. In the present study, we investigated the behavioral phenotypes for the two genders of 3xTg-AD mice at 3, 6, 9, and 12 months old and compared the results with age-, gender-matched C57BL/6N control strain. All mice were subjected to tail flick, pinprick, open field, elevated plus maze, passive avoidance, and trace fear conditioning (TFC) tests to evaluate their sensory, locomotor, anxiety, and learning/memory functions. The results showed that TFC on male 3xTg-AD mice is optimal for studying the memory performance in AD. The sensory and locomotor functions of 3xTg-AD mice for two genders appear to be normal before 6 months, decline in fear memory afterwards. The differences between control and 3xTg-AD male mice in contextual and cued memory are robust, thus they are ideal for evaluating the effect of a treatment. Since it is costly and time consuming to obtain wildtype littermates as controls, C57BL/6N strain is suggested to be used as control mice because their baseline performance of sensorimotor functions are similar to that of 3xTg-AD mice.

The brain regions involved with trace fear conditioning (TFC) and delayed fear conditioning (DFC) are well-characterized, but little is known about the cellular representation subsuming these types of classical conditioning. Previous evidence has shown that activation of the amygdala is required for both TFC and DFC, while TFC also involves the hippocampus for forming conditioned response to tone. Lesions of the hippocampus did not affect tone learning in DFC, but it impaired learning in TFC. Synaptic plasticity in the hippocampus, underlying a cellular representation subsuming learning and memory, is in part modulated by extra-cellular signal-regulated kinase (ERK) signaling pathway. ERK1/2 activation is required for both TFC and DFC during memory formation, but whether this pathway is involved in memory retrieval of TFC is still unknown. In the present study, we investigated changes in ERK1/2 phosphorylation after memory retrieval in groups of mice that received TFC, DFC, tone-shock un-paired conditioning, and naive control. Our results showed that ERK1/2 phosphorylation was elevated in the hippocampal CA1 region after retrieval of all conditioned fear responses. In particular, in the TFC group, immunohistochemistry indicated higher level of ERK1/2 phosphorylation in the hippocampal pyramidal neurons 30 min after tone testing. Inhibition of the ERK1/2 signaling pathway diminished fear memory elicited by a tone in TFC. Together these results suggest that the memory retrieval process in TFC is more dependent on ERK1/2 signaling pathway than that in DFC. ERK1/2 signaling is critical for retrieval associative memory of temporally noncontiguous stimuli.