In summary, our results show that at 12 months of age the CRND8 mice are significantly impaired in both context and cue fear memory, regardless may of the salience of the available conditional stimuli, and that the sensitivity of the delay fear conditioning paradigm to identify the onset of impairment depended on the dynamic range of responses shown by control littermates to more salient foreground tone conditioning. The increased salience of the tone conditioned stimulus, which immediately preceded the foot-shock, resulted in greater sensitivity of the detection of memory deficiency in CRND8 mice due to the stronger shift of the nTg mice to the salience of foreground (tone) stimulus. By inference, our results indicate that the compromised hippocampal-amygdala function in CRND8 mice likely impaired the processing and the use of the more salient conditional tone stimulus [59,60].
It is likely, then, that the impairment in the detection of the salience of the foreground (tone) stimulus reflects subtle differences in the learning ability of CRND8 mice at early stages of amyloid pathology. The comparable context fear memory of the genotypes at three and six months contrasts with the results of our previous studies which demonstrated significant impairment of CRND8 mice in the hippocampus-dependent spatial reference memory evaluated in the water maze test at these ages [26,38]. This discrepancy can be reconciled since the spatial reference memory evaluated in the water or Barnes mazes is not associated with contextual fear memory [61,62] and each of these distinct types of memories might have different underlying mechanisms [63], following different biological functions and adaptive significance.
It is also likely that the change in the salience of the conditioning context [64,65] or switching the context conditioning from background to foreground, by eliminating the delay component of tone presentation, might increase the sensitivity of the context testing paradigm in identifying the impairment of the CRND8 mice in this type of memory at earlier ages. The advantage of the fear conditioning testing paradigm lies in its rapid development of robust and long-lasting memory, which is based on an evolutionary anti-predatory fear response preserved across many species, including humans.
This paradigm, with its long lasting memory of the Batimastat CS-US association provides easier implementation of tests focusing on memory acquisition, forgetting and extinction, and it is less physically demanding than the water maze test. Our study also confirmed the early age of onset [38], followed by rapidly progressing A?? deposition in CRND8 mice. The deposition of A?? plaques increased about 12-fold between three- and six- month and four-fold between six- and 12-month-old mice. This increase in A?? plaque burden was significantly correlated Crenolanib GIST with the decline in contextual and tone fear memory.
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