Dietary cholesterol degrades rabbit long term memory for discrimination learning but facilitates acquisition of discrimination reversal

• Feeding cholesterol to rabbits affects both learning and memory.
• Cholesterol degrades long term memory and facilitates new learning.
• Discrimination reversal can be used to test old memories and new learning.
• Cholesterol may have behavioral effects by modifying hippocampal function.

We have shown previously that feeding dietary cholesterol before learning can improve acquisition whereas feeding cholesterol after learning can degrade long term memory. To examine these different findings within a single paradigm, we fed groups of rabbits 2% cholesterol or normal chow with or without 0.12 ppm copper added to the drinking water following two-tone discrimination learning of the nictitating membrane response in which a 8-kHz tone (conditioned stimulus, CS+) was followed by air puff and a 1-kHz tone (CS−) was not. After eight weeks on the diet, we assessed the rabbits’ conditioned responding during testing and retraining. We then reversed the two-tone discrimination and assessed responding to the 1-kHz tone CS+ and the 8-kHz CS−. During testing, rabbits given cholesterol without copper had lower levels of responding to CS+ than rabbits in the other groups suggesting they did not retain the discrimination as well. However, during a brief discrimination retraining session, their response levels to the CS+ returned to the level of the other groups, demonstrating a return of the memory of the original discrimination. At the end of discrimination reversal, these same rabbits exhibited superior discrimination indexed by lower response levels to CS− but similar levels to CS+, suggesting they were better able to acquire the new relationship between the two tones by inhibiting CS− responses. These results add to our previous data by showing cholesterol diet-induced degradation of an old memory and facilitation of a new memory can both be demonstrated within a discrimination reversal paradigm. Given discrimination reversal is a hippocampally-dependent form of learning, the data support the role of cholesterol in modifying hippocampal function as we have shown previously with in vitro brain slice recordings.