Research report
Working memory in the aged Ts65Dn mouse, a model for Down syndrome

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Abstract

The Ts65Dn mouse displays several phenotypic abnormalities that parallel characteristics found in Down syndrome. One important characteristic associated with Down syndrome is an increased incidence of early-onset Alzheimer's disease. Since Alzheimer's disease is characterized largely by progressive memory loss, it is of interest to study working memory in the Ts65Dn mouse. Previous research in our lab using a titrating, delayed matching-to-position schedule of reinforcement has demonstrated that young, adult male Ts65Dn mice do not display a working memory deficit when compared to age-matched littermate controls. However, there have been no studies examining the working memory of these mice as they age. Due to the correlation between Down syndrome and Alzheimer's disease, and as part of a larger effort to further characterize the phenotype of the Ts65Dn mouse, the purpose of this study was to determine whether aged Ts65Dn mice possess a working memory deficit when compared to age-matched littermate controls.

In order to study working memory, two groups of mice were trained under a titrating, delayed matching-to-position schedule of reinforcement. The first group was trained beginning at 3 months of age, and the second group began training at 15 months of age. Both groups were studied to 24 months of age. Initially, both groups of Ts65Dn mice performed at a lower level of accuracy than the control mice; however, this difference disappeared with further practice. The results from these lifespan studies indicate that the aged Ts65Dn mouse does not possess a working memory deficit when compared to age-matched controls.

Highlights

► Ts65Dn mice took longer to learn the task than did age-matched controls. ► Once the task was mastered, performance was the same between groups. ► Ts65Dn mice do not possess an age-related working memory deficit.

Introduction

Down syndrome, a condition resulting from the presence of three copies of chromosome 21, is the most common genetic cause of mental retardation, occurring in approximately 1 out of every 700 live births [4]. Individuals with Down syndrome possess a range of phenotypic characteristics, including craniofacial abnormalities, muscle hypotonia, and an increased susceptibility to infection. In addition, perhaps the most striking consequence of an extra copy of chromosome 21 is the mental retardation that, although varying in degree, is universally present in individuals with Down syndrome. This mental retardation is manifested clinically by impaired learning and memory [29], [41]. Patients with Down syndrome also display an increased incidence of early-onset Alzheimer's disease, with almost all patients over the age of 35 displaying characteristic Alzheimer-like neuropathology [2], [41].

Experimental animal models are a useful resource for studying many human conditions. Mouse models in particular offer a unique perspective due to the many metabolic and anatomical similarities between mouse and human. The relatively short lifespan and short generation time of the mouse also make these animals an excellent choice in the laboratory. Perhaps more importantly for studying human aneuploid conditions, however, is the considerable genetic similarity between the two species. Specifically, substantial homology exists between human chromosome 21 (HSA21) and mouse chromosomes 10, 16, and 17, with the majority of the conserved segments found on mouse chromosome 16 (MMU16) [21], [38]. The Ts65Dn mouse, developed by Muriel Davisson at The Jackson Laboratory, has a partial trisomy of MMU16. In these mice, 80% of the genes conserved between MMU16 and HSA21 are found in triplicate. Because of this high degree of homology, the Ts65Dn is generally considered the best animal model of Down syndrome [1], [10]. In addition, these mice display several phenotypic abnormalities which parallel those found in humans with Down syndrome. These abnormalities include developmental delays, hyperactivity [11], craniofacial malformations [33], motor dysfunction [6], and learning deficits [18], [35], [40].

Working memory can be defined as a temporary system for maintaining and manipulating information; more simply, it is the memory required to perform accurately on a specific task. Some studies have reported working memory deficits in individuals with Down syndrome [25], [30]. Thus, in an effort to further characterize the phenotype of the Ts65Dn mouse, it is of interest to determine whether these mice also possess working memory deficits. Several methods have been developed to study working memory in laboratory animals. One of the most widely used methods is the Morris water maze, in which the subjects are placed in a tank of water and required to remember the location of a platform hidden under the surface of the water. Studies in the Ts65Dn mouse using the Morris water maze have suggested that these mice do indeed possess working memory deficits [19], [22]. However, the Morris water maze may not be the most appropriate method for studying memory, particularly in the Ts65Dn mouse. Not only can the water maze produce increased levels of stress, which in turn may adversely affect performance, but Ts65Dn mice have demonstrated both slower swimming speeds and significant thigmotaxis (swimming around the perimeter of the water tank), which may make interpretation of results difficult [6], [18].

Behavior can be studied using operant conditioning procedures, which are based on the principle that responses (behavior) are controlled by their consequences. Although it can take a considerable amount of time to train animals under operant procedures, operant conditioning provides several advantages over other methods. Not only can animals be studied without the use of aversive stimuli, but testing can be performed on the same animals for extended periods of time (months or even years). The schedule of reinforcement used to study working memory in these experiments is a titrating, delayed matching-to-position schedule, a modification of the delayed matching-to-sample method developed for use in pigeons [3]. Under this schedule, the animal is required to remember a response position during a delay period and respond at that same position (‘match’) following the delay. A previous study in our lab using this schedule demonstrated that young (3–6 months old) Ts65Dn mice do not show a working memory deficit when compared to littermate controls. Though initially there appeared to be a deficit in the Ts65Dn mice, the discrepancy in performance between the two groups disappeared with further training [17].

The current study represents the first longitudinal study of working memory in the Ts65Dn mouse, which is important for a number of reasons. First, little is known about the cognitive abilities of these mice as they age, and in humans, memory loss is a frequently reported side effect of age. Second, there is a decided link between Down syndrome and Alzheimer's disease. Multiple studies have demonstrated that virtually every person with Down syndrome will eventually display the characteristic neuropathology of Alzheimer's disease [9], [24], [42], [43], [26]. Though the Ts65Dn mouse does not exhibit amyloid plaques or neurofibrillary tangles, they do show an age-related degradation of basal forebrain cholinergic neurons (BFCN), similar to that seen in Alzheimer's disease [5], [20], [27], [36]. This leads to our hypothesis that an accelerated decline in working memory, compared to their euploid littermates, will be observed in Ts65Dn mice as they age. Thus, the purpose of the studies reported here was to determine whether an age-related deficit in working memory is present in the Ts65Dn mouse.

Section snippets

Animals

Twenty-five male Ts65Dn mice and 25 male littermate control (LC) mice were obtained from The Jackson Laboratories (Bar Harbor, ME). All mice were genotyped and screened for retinal degeneration before being shipped. Beginning at approximately 3 months of age, animals were housed individually and maintained on a 12-h light/dark cycle. The animals were given water ad libitum and food deprived to 85% of their free-feeding weights.

Apparatus

Subjects were tested in four Med Associates (St. Albans, VT) Modular

Group 1 mice

When trained under the matching-to-position schedule with a fixed 3-s delay, both Ts65Dn and LC mice initially performed at around chance accuracy. After 20 days of training, both lines had improved, but the LC displayed significantly greater matching accuracy than their trisomic counterparts (Fig. 1). However, within a few weeks after the implementation of the delay titration, the Ts65Dn mice were achieving mean delays per session that were not significantly different from the LC mice (Fig. 2

Discussion

Previous research from our lab has indicated that under a delayed matching-to-position procedure, young Ts65Dn mice display no working memory deficit when compared to euploid controls [17]. Data reported in the present study for mice in Group 1 show that we replicate these findings here: during initial training using a fixed 3-s delay, the Ts65Dn mice performed at a significantly lower percent accuracy in matching than the LC mice, suggesting that a memory deficit is present in the trisomic

Acknowledgments

The authors would like to thank Dr. D. Keith Williams for providing input on statistical analyses, and both Dr. Nichole Sanders and Camron Hall for help and support in the laboratory. This work was supported by NICHD grant HD047656 (G.R. Wenger).

References (43)

  • C.L. Hunter et al.

    Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory

    Behavioural Brain Research

    (2003)
  • T.M. Pham et al.

    Effects of environmental enrichment on cognitive function and hippocampal NGF in the non-handled rats

    Behavioural Brain Research

    (1999)
  • N.C. Sanders et al.

    Does the learning deficit observed under an incremental repeated acquisition schedule of reinforcement in Ts65Dn mice, a model for Down syndrome, change as they age?

    Behavioural Brain Research

    (2009)
  • H. Seo et al.

    Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice

    Experimental Neurology

    (2005)
  • E.C. Akeson et al.

    Ts65Dn – localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome

    Cytogenetics and Cell Genetics

    (2001)
  • D.S. Blough

    Delayed matching in the pigeon

    Journal of the Experimental Analysis of Behavior

    (1959)
  • M.A. Canfield et al.

    National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001

    Birth Defects Research. Part A, Clinical and Molecular Teratology

    (2006)
  • A.J. Dalton et al.

    Incidence of memory deterioration in aging persons with Down's syndrome

  • M.T. Davisson et al.

    Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome

  • M.T. Davisson et al.

    Segmental trisomy as a mouse model for Down syndrome

  • G. Dawson et al.

    Neuropsychological correlates of early symptoms of autism

    Child Development

    (1998)
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