Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.

The hippocampus is believed to be an important structure for learning tasks that require temporal processing of information. The trace classical conditioning paradigm requires temporal processing because the conditioned stimulus (CS) and the unconditioned stimulus (US) are temporally separated by an empty trace interval. The present study sought to determine whether the hippocampus was necessary for rats to perform a classical trace fear conditioning task in which each of 10 trials consisted of an auditory tone CS (15‐s duration) followed by an empty 30‐s trace interval and then a fear‐producing floor‐shock US (0.5‐s duration). Several weeks prior to training, animals were anesthetized and given aspiration lesions of the neocortex (NEO; n = 6), hippocampus and overlying neocortex (HIPP; n = 7), or no lesions at all (control; n = 6). Approximately 24 h after trace conditioning, NEO and control animals showed a significant decrease in movement to a CS‐alone presentation that was indicative of a conditioned fear response. Animals in the HIPP group did not show conditioned fear responses to the CS alone, nor did a pseudoconditioning group (n = 7) that was trained with unpaired CSs and USs. Furthermore, all groups except the HIPP group showed conditioned fear responses to the original context in which they received shock USs. One week later, HIPP, NEO, and control animals received delay fear‐conditioning trials with no trace interval separating the CS and US. Six of seven HIPP animals could perform the delay version, but none could perform the trace version. This result suggests that the trace fear task is a reliable and useful model for examining the neural mechanisms of hippocampally dependent learning. Hippocampus 1998;8:638–646. © 1998 Wiley‐Liss, Inc.

The goal of this study was to determine whether trace eyeblink conditioning is a hippocampally dependent associative learning task in the mouse. First, we examined trace intervals of 0, 250, and 500 ms to determine a relatively long trace interval that would support eyeblink conditioning in young adult C57BL/6 mice. Mice rapidly acquired conditioned responses (CRs) with a 0-ms trace interval, acquired CRs with a 250-ms trace interval in approximately 2 days (2 sessions per day), and showed little acquisition with a 500-ms trace interval. Control mice were presented randomly unpaired stimuli and failed to show conditioning. We then determined the effect of lesioning dorsal hippocampal neurons on trace eyeblink conditioning. The hippocampus was injected bilaterally with vehicle (phosphate-buffered saline), 0.1% ibotenic acid, or 1% ibotenic acid. The vehicle group showed >60% CRs. The 0.1% group showed significantly fewer CRs (35-45%). The 1% group showed a level of CRs similar to that of the control mice. All the lesioned mice exhibited >60% CRs when subsequently trained with a 0-ms trace interval. A regression analysis indicated that the volume of area CA1 lesioned was more predictive of the behavioral impairment than the lesion volume of either CA3 or dentate gyrus, or even the total lesion volume. We conclude that dorsal hippocampal neurons play a critical role in eyeblink conditioning when a 250-ms trace interval is used with the C57BL/6 mouse, and that this paradigm will be useful for studying behavior and the in vivo and in vitro electrophysiology of hippocampal neurons in normal and transgenic or knockout mice.

This study sought to determine whether CA1 hippocampal neurons encode the duration of the trace interval during trace fear conditioning. Single neurons were recorded extracellularly in the CA1 of rabbits during and after a single trace fear classical conditioning session. Trace fear conditioning trials consisted of an auditory conditioned stimulus (CS; 3 sec) and a fear-producing shock unconditioned stimulus (US; 0.5 sec) separated by a silent trace interval. One group of rabbits was trained using a 10 sec trace interval (n = 5), and another group was trained using a 20 sec trace interval (n = 4). These groups were compared with pseudoconditioning control rabbits (n = 5 and n = 4, respectively) that received unpaired CSs and USs. One day after trace and pseudo fear conditioning rabbits received a CS-alone retention session in which no USs were presented. The trace conditioned groups showed larger bradycardiac-fear responses on CS-alone trials compared with the pseudoconditioning groups. A significant percentage of CA1 neurons from the 10 and 20 sec trace groups (24 and 28%, respectively) showed maximal firing on CS-alone retention trials timed to 10 sec (+/-1.5 sec) and 20 sec (+/-2.0 sec) after CS offset, respectively. These latencies were similar to the duration of the trace interval used on previous CS-trace-US trials. Timed CA1 firing was not seen in pseudoconditioning control animals, suggesting that a subset of CA1 neurons encoded the trace interval duration. The percentage of neurons encoding trace duration was largest when rabbits exhibited significant fear responses to the CS, suggesting that trace encoding was related to the strength of the CS and US association.

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Little is known about signaling mechanisms underlying temporal associative learning. Here, we show that mice with a targeted point mutation that prevents autophosphorylation of ␣CaMKII (␣CaMKII T286A ) learn trace eyeblink conditioning normally. This forms a sharp contrast to the severely impaired spatial learning in the water maze and contextual fear conditioning observed in ␣CaMKII T286A mutants. Importantly, hippocampal lesions impaired trace eyeblink conditioning in ␣CaMKII T286A mice, suggesting a potential role of hippocampal ␣CaMKII-independent mechanisms. These results indicate that hippocampal signaling mechanisms that underlie temporal associative learning as assessed by trace eyeblink conditioning may differ from those of spatial and contextual learning.