Contextual learning and cue association in fear conditioning in mice: a strain comparison and a lesion study

Fear conditioning with electric shock (unconditioned stimulus, US) paired with tone cue (conditioned stimulus, CS) has been extensively applied in recent molecular neurobiological analysis of hippocampal dysfunction in mice because the context-dependent test phase of this learning paradigm is claimed to detect hippocampal impairment in a specific manner, whereas the cue-dependent test serves as a control situation independent of hippocampal function. These claims are based on hippocampal lesion studies performed with rats and have not been conclusively confirmed with mice with specific hippocampal lesion. Therefore, I investigated how hippocampal ibotenic acid lesion affects conditioned fear in mice. I confirm that extensive lesions localized to the hippocampus impair context-dependent learning but also show that, unlike in the original rat studies, the behavioral impairment is only partial. Furthermore, studying two inbred strains of mice (C57BL/6 and DBA/2) with highly different hippocampal function, I show that the presence or absence of CS during training may influence the mouse's ability to learn complex multiple contextual stimuli in a genotype-dependent manner. I conclude that performance at the 'context' test may be based on complex configural (hippocampal) learning but it can also be based on a more simple elemental (non-hippocampal) learning thus leading to potentially false-negative findings in the analysis of hippocampal dysfunction.