The strength of both types of memory in this paradigm is inferred from the same behavior of freezing response to relevant conditioned stimuli. The implementation of the delay fear conditioning paradigm, in which an explicit cue such as a tone is co-terminated with a foot-shock, usually results in stronger foreground conditioning to tone and weaker conditioning to neverless background contextual cues [54]. Our study confirmed this prediction and demonstrated that nTg control mice had a stronger conditioned tone fear memory than a context fear memory. In contrast, the foreground fear conditioning to tone did not differentiate the response of CRND8 mice from their response to the background context cues. The apparent dissociation in the onset of the cognitive impairment of CRND8 mice in the delay conditioning paradigm has important practical consequences.

First, it stresses the importance of the comparative analysis between genotypes across multiple tasks, which differ in the strength of memory development, in order to identify the ceiling performance or maximum dynamic range of the control nTg mice maintained on a specific genetic background. Second, the comparison between the tasks demonstrated that not only the impairment of CRND8 mice declined with age, but they also were not able to reach a level of performance comparable to nTg controls at the earlier ages of testing when the A?? plaque burden was relatively low. Moreover, the CRND8 mice showed impairment in generalizing the conditioning effects to additional cues present in the testing room, such as characteristics of sound attenuating chambers or other subtle cues, which despite our effort, could not be completely eliminated during the tone test.

Consequently, their freezing rates during the pre-tone phase of the test were significantly lower than the freezing of nTg littermates, especially at older ages. Our results also indicated that the 12-month-old nTg control mice showed slightly lower, albeit not significant, freezing rates. Although aged, 19- to 20-month-old, Carfilzomib C57BL/6 mice show impairment in the fear conditioning memories [55], additional studies should establish whether the decrease in the fear conditioned freezing response occurs reliably at much earlier ages in the hybrid C57BL/6//C3H background of the CRND8 model. Future studies should also extend our findings and focus on testing the CRND8 mice at ages preceding overt amyloid-?? MEK162 buy deposition, in an attempt to elucidate whether the impairment in conditioned fear memory in this model contains an age-independent component [56], caused by the constitutive expression of the APP transgene.