Aims: Exploring the neurobiological mechanisms of early AD damage Background: The early diagnosis of Alzheimer's disease (AD) has a very important impact on the prognosis of AD. However, the early symptoms of AD are not obvious and difficult to diagnose. Existing studies have rarely explored the mechanism of early AD. AMPARs are early important learning memory-related receptors. However, it is not clear how the expression levels of AMPARs change in early AD. Objective: We explored learning memory abilities and AMPAR expression changes in APP/PS1 mice at 4 months, 8 months, and 12 months. Method: We used the classic Morris water maze to explore the learning and memory impairment of APP/PS1 mice and used western blotting to explore the changes in AMPARs in APP/PS1 mice. Result: We found that memory impairment occurred in APP/PS1 mice as early as 4 months of age, and the impairment of learning and memory gradually became serious with age. The changes in GluA1 and p-GluA1 were most pronounced in the early stages of AD in APP/PS1 mice. Conclusion: Our study found that memory impairment in APP/PS1 mice could be detected as early as 4 months of age, and this early injury may be related to GluA1.

Background: Conditioned place preference (CPP) is a common behavioral paradigm for studying the association of unconditioned stimulus reward memory with context.Generalization is a flexible memory recall pattern developed on the basis of original memory. Drug-seeking behaviors in substance use disorders (SUDs) exhibit diversity, which we generally attribute to the highly generalized features of SUD memory.However, to date, there are no animal models for SUD generalization studies. Methods:We design the generalization box (G-box) and the generalization retrieval process based on the conditioned place preference (CPP) model. In the memory retrieval stage, we replaced the conditioning CPP box (T-box) with a generalization box (G-box) to study drug generalization memory. For appearance, the generalized boxes have different angles and numbers of sides compared to the conditioning boxes. For the visual cues, the shapes of the symbols are different (triangle icons for the hexagonal chamber and dot icons for the round chamber), but the orientation information remains the same. To establish CPP generalization, the mice received morphine on the vertical or horizontal side of a conditioning box (T-box) and saline on the other side.Then, after CPP conditioning, the generalization test was performed in a generalization box (G-box: hexagonal chamber and Gr-box: round chamber) 21 days later.Results: CPP-conditioned mice still displayed a clear preference for similar visual information in the G-box. CPA-conditioned mice behaved similarly to CPP, with mice consistently avoiding similar visual information in the G-box. We further observed that the generalization results are similar using two generalization boxes (G-box and Gr-box). Conclusion:In this study, we succeeded in creating a simple and effective generalization model for morphine reward. The establishment of this model provides a new tool for generalization studies of SUD and therapy in humans.

An obvious reason for substance uses disorders (SUDs) is drug craving and seeking behavior induced by conditioned context, which is an abnormal solid context memory. The relationship between susceptibility to SUD and learning ability remains unclear in humans and animal models. In this study, we found that susceptibility to morphine use disorder (MUD) was negatively correlated with learning ability in conditioned place preference (CPP) in C57 mice. By using behavioral tests, we identified the FVB mouse as learning impaired. In addition, we discovered that learning-relevant proteins, such as the glutamate receptor subunits GluA1, NR1, and NR2A, were decreased in FVB mice. Finally, we assessed the context learning ability of FVB mice using the CPP test and priming. We found that FVB mice had lower learning performance with respect to normal memory but higher performance of morphine-reinstatement memory. Compared to C57 mice, FVB mice are highly sensitive to MUDs. Our results suggest that SUD susceptibility is predicted by impaired learning ability in mice; therefore, learning ability can play a simple and practical role in identifying high-risk SUD groups.