A novel paradigm for assessing olfactory working memory capacity in mice

Geng-Di Huang,Li-Xin Jiang,Chen Zhang,Hua-Li Wang,Xin Yu,Feng Su

doi:10.1038/s41398-020-01120-w

Geng-Di Huang, Li-Xin Jiang + Show 4 more

Open Access

https://doi.org/10.1038/s41398-020-01120-w

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Abstract

A decline in working memory (WM) capacity is suggested to be one of the earliest symptoms observed in Alzheimer’s disease (AD). Although WM capacity is widely studied in healthy subjects and neuropsychiatric patients, few tasks are developed to measure this variation in rodents. The present study describes a novel olfactory working memory capacity (OWMC) task, which assesses the ability of mice to remember multiple odours. The task was divided into five phases: context adaptation, digging training, rule-learning for non-matching to a single-sample odour (NMSS), rule-learning for non-matching to multiple sample odours (NMMS) and capacity testing. During the capacity-testing phase, the WM capacity (number of odours that the mice could remember) remained stable (average capacity ranged from 6.11 to 7.00) across different testing sessions in C57 mice. As the memory load increased, the average errors of each capacity level increased and the percent correct gradually declined to chance level, which suggested a limited OWMC in C57 mice. Then, we assessed the OWMC of 5 × FAD transgenic mice, an animal model of AD. We found that the performance displayed no significant differences between young adult (3-month-old) 5 × FAD mice and wild-type (WT) mice during the NMSS phase and NMMS phase; however, during the capacity test with increasing load, we found that the OWMC of young adult 5 × FAD mice was significantly decreased compared with WT mice, and the average error was significantly increased while the percent correct was significantly reduced, which indicated an impairment of WM capacity at the early stage of AD in the 5 × FAD mice model. Finally, we found that FOS protein levels in the medial prefrontal cortex and entorhinal cortex after the capacity test were significantly lower in 5 × FAD than WT mice. In conclusion, we developed a novel paradigm to assess the capacity of olfactory WM in mice, and we found that OWMC was impaired in the early stage of AD.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia in elderly individuals, is characterised by progressive loss of cognitive abilities[1,2,3]
The analysis showed that the performance accuracy (F7, 56 = 8.02, p < 0.001; Fig. 2A), correct option rate (F7, 56 = 17.19, p < 0.001; Fig. 2B), and correct rejection rate (F7, 56 = 5.35, p < 0.001; Fig. 2B) gradually increased during the non-matching to a single-sample odour (NMSS) rule-learning phase, and the post hoc analysis revealed no significant differences between the last two sessions
In 5 × FAD transgenic mice, an animal model of AD, we found that the olfactory working memory capacity (OWMC) of transgenic mice was significantly reduced compared with WT mice, indicating the impairment of working memory (WM) capacity in 5 × FAD mice

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia in elderly individuals, is characterised by progressive loss of cognitive abilities[1,2,3]. Most research has focused on understanding the relationship between memory impairments and the pathological hallmarks of the disease, namely, the presence of amyloid-beta (Aβ) accumulation in amyloid plaques, tau aggregation in neurofibrillary tangles and brain atrophy caused by loss of neurons and synapses[4,5]. A reliable and objective means of WM in AD are thought to contribute to a range of significant problems, such as difficulties in dividing attention and manipulating remembered information[11]. Huang et al Translational Psychiatry (2020)10:431 individuals have difficulty recalling items, indicating a deficit in WM in the early stages of AD8. Uncovering the mechanism underlying WM may aid in developing measures to prevent memory impairment in AD13

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