Sex differences shape memory capacity decline during ageing

Memory Capacity (MC) is the amount of information that can be held in memory for a specific time interval. It is known to be regulated by fronto-striatal dopamine circuit and hippocampus (HP), in low and high memory load conditions, respectively. Using the Different and the Identical Object Recognition Task (DOT/IOT), we have shown that adult male mice discriminate 3, 4, 6 but not 9 different objects after a delay of 1 min or 24 hr. Moreover, we have demonstrated that male mice use the HP to solve the task only in high memory load condition (6-DOT; Sannino et al 2012, Olivito et al 2014), similar to humans. Although gender differences in humans are reported, less is known about the mechanisms underlying these differences. To study the role of sex differences in influencing MC, we have challenged female and male mice with different number of objects to remember for short- or long-term retention intervals. We have found that female mice have a load- and time- dependent memory deficit, since they perform the 6-DOT at 1 min but not at 24hr retention interval. Using a combination of ex-vivo brain activation imaging and in vivo brain activity manipulation techniques we are testing the hypothesis that female mice use a different neuronal circuitry to solve the task in condition of high memory load. The first approach, through c-fos brain mapping, revealed that female mice activate the dorsal HP to a lesser extent compared to male mice. Western blot analysis performed on dorsal HP of these mice further confirmed the different hippocampal recruitment between male and female mice. With a second approach, interestingly, by stimulating the dorsal HP of female mice through DREADDs, we rescued the memory impairment found in these mice. To compare the course of MC performance with ageing, we tested 6 and 12 months old male and female mice in the DOT/IOT. We found that while male mice show a load-dependent impairment only at 12 months old, the same deficit is anticipated at 6 months in female subjects. Our results suggest that female subjects use different memory circuitry than male in high memory load conditions, which may yield to higher vulnerability of memory insults with ageing. Our data might be relevant to understand the higher impact of age-related dementia and Alzheimer’s disease in women compared to men.