Enhanced Medial Prefrontal Cortex and Hippocampal Activity Improves Memory Generalization in APP/PS1 Mice: A Multimodal Animal MRI Study

Abstract

Memory generalization allows individuals to extend previously learned movement patterns to similar environments, contributing to cognitive flexibility. In Alzheimer's disease (AD), the disturbance of generalization is responsible for the deficits of episodic memory, causing patients with AD to forget or misplace things, even lose track of the way home. Cognitive training can effectively improve the cognition of patients with AD through changing thinking mode and memory flexibility. In this study, a T-shaped maze was utilized to simulate cognitive training in APP/PS1 mice to elucidate the potential mechanisms of beneficial effects after cognitive training. We found that cognitive training conducted by a T-shaped maze for 4 weeks can improve the memory generalization ability of APP/PS1 mice. The results of functional magnetic resonance imaging (fMRI) showed that the functional activity of the medial prefrontal cortex (mPFC) and hippocampus was enhanced after cognitive training, and the results of magnetic resonance spectroscopy (MRS) showed that the neurochemical metabolism of N-acetyl aspartate (NAA) and glutamic acid (Glu) in mPFC, hippocampus and reuniens (Re) thalamic nucleus were escalated. Furthermore, the functional activity of mPFC and hippocampus was negatively correlated with the escape latency in memory generalization test. Therefore, these results suggested that cognitive training might improve memory generalization through enhancing the functional activity of mPFC and hippocampus and increasing the metabolism of NAA and Glu in the brain regions of mPFC, hippocampus and Re nucleus.

Keywords: Alzheimer’s disease; cognitive training; functional activity; generalization; neurochemical metabolism.

FIGURE 1

Experimental design. (A) The detailed time line of this experiment. (B) The schematic graph of water T-maze cognitive training. (C) The schematic graph of the Morris water maze and memory generalization test.

FIGURE 2

The course of the memory flexibility training in APP/PS1 mice. (A) The correct rate in the learning and memory stage. (B) The correct rate in the memory flexibility training stage.

FIGURE 3

Cognition performance after cognitive training in APP/PS1 mice. (A–E) Learning memory and memory generalization ability after cognitive training. (A) The escape latency of each group in the Morris water maze. (B) The escape platform crossing times of each group in the Morris water maze. (C) The escape latency of each group in the memory generalization test. (D) Representative diagram of each group in the space exploration experiment. (E) Representative diagram of each group in the memory generalization test. *P < 0.05 compared with the WT group, **P < 0.01 compared with the WT group, ***P < 0.001 compared with the WT group, ^#P < 0.05 compared with the AD group, ^##P < 0.01 compared with the AD group.

FIGURE 4

Changes in brain functional activity after cognitive training in APP/PS1 mice. (A) The ReHo value of the AD group decreased significantly compared with the WT group. (B) The ReHo value of the Cog-group increased compared with the AD group.

FIGURE 5

Correlations between functional activity and memory generalization ability. (A) Correlation between the functional activity of mPFC and memory generalization ability. (B) Correlation between the functional activity of hippocampus and memory generalization ability.

FIGURE 6

Changes in neurochemical metabolism after cognitive training in APP/PS1 mice. (A–E) The neurochemical metabolism of Glu and NAA of each group in mPFC (left), mPFC (right), hippocampus (left), hippocampus (right), and Re nucleus. (F) The location and the representative graph in mPFC (left), mPFC (right), hippocampus (left), hippocampus (right), and Re nucleus. *P < 0.05 compared with the WT group, ^**P < 0.01 compared with the WT group, ^***P < 0.001 compared with the WT group, ^#P < 0.05 compared with the AD group, ^##P < 0.01 compared with the AD group, ^###P < 0.001 compared with the AD group.