Fos imaging reveals ageing-related changes in hippocampal response to radial maze discrimination testing in mice

A two-stage radial arm maze (RAM) task has been designed recently to demonstrate a specific age-related memory deficit in mice. It highlights the contrast between normal and deficient memory expression in a spatial discrimination problem depending on how to-be discriminated arms were presented to the animal. This specific deficit has been interpreted as a preferential loss in a relational/declarative form of memory, thereby implying an underlying hippocampal dysfunction. To test this hypothesis, neuronal activation measured by Fos immunostaining was compared in aged (21-23 months) and adult (4-6 months) mice trained in the aforementioned task and killed after a retention session consisting in age-insensitive probe trials, performed 6 days later (6-day RAM). Two comparison conditions were included: (i) repeated locomotor training on a treadmill (TM); (ii) the same RAM training, except for the use of a longer (30 days instead of six) retention interval (30-day RAM). Although all RAM groups displayed similar levels of performance at the end of the experiment, immediately before the mice were killed, significant between-group differences in brain activation were observed. In adult mice, 6-day RAM testing was associated with greater septal and hippocampal (CA1, CA3, DG) Fos expression than the TM condition. Lengthening the retention interval from 6 days to 30 days resulted in a significant decrease in RAM testing-induced Fos expression in most of the septo-hippocampal regions. With respect to adult mice, aged mice displayed reduced Fos expression (except for DG) and a lack of interrelationships between levels of Fos produced in each of the SH regions, in the 6-day RAM testing condition. Conversely, there was no effect of ageing on Fos expression associated with either TM training or 30-day RAM testing. These results are interpreted as reflecting age- (or time-) related alterations in recruiting of brain structures that underlie a relational/declarative form of memory expression.