Superior Place Learning of C57BL/6 vs. DBA/2 Mice Following Prior Cued Learning in the Water Maze Depends on Prefrontal Cortical Subregions

Abstract

The participation of the prefrontal cortex (PFC), hippocampus, and dorsal striatum in switching the learning task from cued to place learning were examined in C57BL/6 and DBA/2 mice, by assessing changed levels of phosphorylated CREB (pCREB). Mice of both strains first received cued training in a water maze for 4 days (4 trials per day), and were then assigned to one of four groups, one with no place training, and three with different durations of place training (2, 4, or 8 days). Both strains showed equal performance in cued training. After the switch to place training, C57BL/6 mice with 2 or 4 days of training performed significantly better than DBA/2 mice, but their superiority disappeared during the second half of an 8 days-place training period. The pCREB levels of these mice were measured 30 min after place training and compared with those of mice that received only cued training. Changes in pCREB levels of C57BL/6 mice were greater in the hippocampal CA3, hippocampal dentate gyrus, orbitofrontal and medial PFC than those of DBA/2 mice, when mice of both received the switched place training for 2 days. We further investigated the roles of orbitofrontal and medial PFC among these brain regions showing strain differences, by destroying each region using selective neurotoxins. C57BL/6 mice with orbitofrontal lesions were slower to acquire the place learning and continued to use the cued search acquired during the cued training phase. These findings indicate that mouse orbitofrontal cortex (OFC) pCREB is associated with behavioral flexibility such as the ability to switch a learning task.

4-Hydroxynonenal Immunoreactivity Is Increased in the Frontal Cortex of 5XFAD Transgenic Mice

“…Most studies of 5XFAD mice have investigated Aβ deposition in brain regions, including the hippocampus which is responsible for memory impairments. Our quantitative analysis of regional Aβ42 deposition in 6-month-old 5XFAD mice using ELISA revealed that levels were highest in the hippocampus, followed by the cortex, then the striatum [19]. The present analysis of regional Aβ42 deposition in 4-month-old 5XFAD mice using immunofluorescence staining exhibited differences between the 5XFAD and non-Tg mice in the frontal cortex and hippocampus, but not in the striatum.…”

“…Procedural knowledge of the task acquired in the prior cued training has been reported to interfere with the use of the spatial strategy needed to perform the place task efficiently more in 6-month-old 5XFAD mice than non-Tg control mice [ 20 ]. Therefore, we divided place training into two sessions (the first 8 trials and second 8 trials) and analyzed the search patterns of mice using criteria mentioned earlier ( Figure 1 B) [ 19 , 20 , 24 ]. Student’s t -test on the percentage of mice that used a spatial strategy in the place training revealed that 4-month-old 5XFAD mice used this strategy less than non-Tg mice in both sessions (session 1, t (26) = 2.957, p < 0.005; session 2, t (26) = 4.170, p < 0.001; Figure 1 B).…”

“…The frontal cortex, including the prefrontal cortex, is also known to be critically engaged in strategy switching [19,29,30]. We previously reported that 3-month-old C57BL/6 mice with lesions of medial prefrontal cortex or orbitofrontal cortex exhibited continued use of the cued search strategy acquired during cued training in the switched place training phase [19]. We also examined 6-month-old 5XFAD mice's performance in the same learning strategy-switched task and observed the same behavioral pattern as that seen in mice with prefrontal cortex lesions.…”

“…Each mouse serially received a cued/response and place/spatial version of the water maze task, adopted from McDonald and White [14] and modified in our previous studies [17,[19][20][21]. Briefly, each mouse received cued/response training for 4 days, followed by place/spatial training for four days.…”

“…For example, in the water maze task, a place/spatial learning (place) strategy requiring the use of spatial cues depends critically on the hippocampus, whereas a cued/response (cued) learning strategy using egocentric navigation/instrumental learning relies on the striatum. In addition, the prefrontal cortex engages in switching from the used learning strategy to a new strategy [18,19]. Recent studies have reported that oxidative damage is observed in the frontal cortex in early AD [1][2][3], and 4-month-old 5XFAD mice may reflect the cognitive and neuropathological features of early AD.…”