CALORIC RESTRICTION IMPROVES SPATIAL LEARNING BUT NOT COGNITIVE FLEXIBILITY IN MALE AND FEMALE TGF344-AD RATS

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, characterized by early impairments in spatial memory and executive functions, with its onset and progression influenced by lifestyle factors, including diet. Caloric restriction (CR) - a reduction of the caloric intake without inducing malnutrition - has been proposed as a potential non-pharmacological intervention to delay cognitive decline, although its effects on different cognitive domains during AD progression and possible sex differences remain unclear. Here, we evaluated the effects of long-term CR on spatial memory and cognitive flexibility in male and female TgF344-AD rats, a well-established rat model of AD. At postnatal day 90, animals were randomly assigned to CR or ad libitum feeding. At 12 months of age, spatial learning and memory were assessed using the Morris Water Maze (MWM), including acquisition training, a probe memory test, and reversal learning. Caloric restriction improved performance in both male and female TgF344-AD rats compared with ad libitum-fed animals, but no differences were detected in target quadrant occupancy during the probe memory trial. In reversal trials, transgenic males were impaired independently of diet, with a comparable trend in females, consistent with persistent deficits in cognitive flexibility. Overall, these findings indicate that long-term CR selectively benefits learning performance, but not cognitive flexibility in TgF344-AD rats. Such effects involve the use of alternative navigation strategies in MWM, and the modulation of AD-related neurodegenerative and inflammatory processes.