Effects of working memory training on cognitive flexibility, dendritic spine density and long-term potentiation in female mice.

Working memory (WM) is a cognitive ability that allows the short-term maintenance and manipulation of information for goal-directed behavior. The prefrontal cortex (PFC) and the hippocampus (HPC) are two brain regions implicated in WM task performance. Several studies indicate that training in WM (WMT) can enhance performance in various other cognitive tasks. However, our understanding of the neurobiological changes induced by WMT is very limited. Previous work from our lab showed that WMT enhances synaptic and structural plasticity in the PFC and HPC in male mice. In this study, we investigate the effect of WMT on cognitive flexibility and synaptic properties in PFC and HPC in adult female mice. To this end, female adult mice were split into 3 groups: a) mice that remained in their home cage (naïve), b) mice that performed the alternation task in the T-maze (non-adaptive) and c) mice that were trained in the delayed alternation task for 9 days (adaptive). The delayed alternation task was used for WMT. In one cohort, following the delayed alternation task, all mice were tested in the attention set-shifting (AST) task to measure cognitive flexibility, followed by harvesting of the brains for Golgi-Cox staining to study dendritic spine density. Our results showed that in female mice, there were no differences in AST performance among the three groups tested, however, the latency to make a choice was reduced in the adaptive group. With regards to dendritic spine density, no significant differences were identified in PFC while increased dendritic spine density was found in HPC of the adaptive group, compared to the naïve group. In a second cohort, acute brain slices were prepared after completion of the delayed alternation task to investigate the synaptic properties in the PFC and the HPC. Evoked field excitatory post-synaptic potential (fEPSP) recordings were performed in either PFC or HPC brain slices. Our results show that tetanic-induced long-term potentiation (LTP) in the PFC was not different among the three training groups. In the HPC, theta-burst induced LTP was significantly increased in the adaptive group also compared to the non-adaptive and naïve groups. These results reveal both similarities and differences of WMT on performance in the attention set-shifting task, dendritic spine density and LTP in females, compared to males.