Elsevier

Behavioural Brain Research

Volume 163, Issue 2, 8 September 2005, Pages 174-185
Behavioural Brain Research

Research report
Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome

https://doi.org/10.1016/j.bbr.2005.04.016Get rights and content

Abstract

Ts65Dn mouse is the most widely accepted model for Down syndrome. We previously showed that environmental enrichment improved spatial learning in female but deteriorated it in male Ts65Dn mice. This study analyzed the factors contributing to the disturbed cognition of male Ts65Dn mice after enriched housing, by allocating male control and Ts65Dn mice in four conditions after weaning: small (n = 2–3) and large group (n = 8–10) housing, and enriched housing in small (2–3) and large groups (8–10). Learning, aggressive behavior, anxiety-like behavior and biochemical correlates of stress were evaluated when Ts65Dn and control mice were 4–5 months old. Environmental enrichment in large mixed colonies of Ts65Dn and diploid littermates disturbed behavioral and learning skills of Ts65Dn mice in the Morris water maze. ACTH and testosterone levels were not modified in any group of mice. Ts65Dn and control mice subjected to enriched housing in large groups and Ts65Dn mice housed in large groups showed higher corticosterone levels. Aggressive behavior was evaluated by measuring the number of attacks performed in the presence of an intruder. Ts65Dn mice performed less attacks than controls in all conditions, especially after enriched housing, indicating subordination. In the plus maze, cognitive aspects (i.e. risk assessment) and motor components (open arm avoidance) of anxiety behavior were evaluated; no difference in any condition was found. It is suggested that an excess of social and/or physical stimulation in Ts65Dn mice may affect cognition by disturbing the emotional and behavioral components of the learning process.

Introduction

The most commonly used murine model of Down syndrome (DS) is the Ts65Dn (TS) mouse, which is trisomic for the region of mouse chromosome 16 orthologous to human chromosome 21, spanning the region just proximal to Gabpa/App gene cluster to Znf295 [26]. Several phenotypic properties of individuals with DS are found in this mouse model. Limiting to the central nervous system features, TS mice show significant disturbances which are similar to those found in the human condition. Neural morphology is altered showing reductions in size and number of neurons of different cerebral areas, neuronal degeneration and modifications in synaptic size and number [1], [2], [16], [27], [31], [33], [38], [39]. Functional studies have also shown similar failures in relevant signaling systems [13], [17], [18], [41], [42], [56] and electrophysiological properties [24], [25], [35], [57], [58]. At the behavioral level, both, Down syndrome patients and TS mice, have shown developmental delay, reduced capacity of attention and alterations in different processes involved in learning and memory [19], [20], [22], [31], [62]. Finally, similarly to what is observed in DS, Ts65Dn mice age sooner, show reduced response to painful stimuli, and present immunological alterations [44], [49].

One of the main objectives of DS research is to develop strategies that might improve the intellectual disability, the most disturbing and consistent consequence of this chromosomal anomaly. In an attempt to test whether cerebral plasticity could be compromised by the trisomy, we analyzed the influence of enriched environment on learning and memory abilities [45], and neocortical pyramidal cell phenotype [16] of Ts65Dn mice. Environmental enrichment is known to enhance the expression of a number of genes related to neural structure and plasticity [52], and, consequently, to increase several morphological [15], [51], neurochemical [3], [5], [6], [9], [10], [21], [40], [52], [55], [60], [61] and behavioral parameters [21], [23], [47], [50]. We showed that environmental enrichment could modify learning and memory abilities in TS mice [45]. However, these changes were gender dependent: environmental enrichment improved learning and memory in female TS mice but deteriorated these abilities in males.

It is known that the behavioral profile of male mice is particularly sensitive to environmental changes, especially those involving modifications in dominance hierarchy, a factor that can be easily introduced in the enrichment setting. In addition, an increment in any stressor condition, including aggressiveness, may interfere with the performance in different hippocampus dependent learning and memory tasks [12]. The purpose of the present study was, therefore, to evaluate the way in which housing TS mice in different environmental conditions may influence upon: (a) several biochemical and behavioral stress parameters, (b) the effect on different components of the anxiety response and (c) the performance in the Morris water maze test.

Section snippets

Animals

Ts65Dn segmental trisomic mice were bred in the Faculty of Medicine colony, from TS females and B6EiC3HF1male breeders provided by the Robertsonian Chromosome Resources (The Jackson Laboratory, Harbor Bar, Maine, USA). In all the experiments mice with partial trisomy were compared to disomic controls (CO) from the same litters. Trisomy was determined by karyotyping the animals at the age of 6–8 weeks following the method of Davisson and Akeson [11]. Because C3H/HeSnJ mice carry a recessive

Biochemical parameters

No significant differences were observed between CO and TS mice in any of the environmental conditions for plasma concentrations of ACTH [F(7,106) = 1.33, n.s.] (Fig. 1A) and testosterone [F(7,96) = 0.96, n.s.] (Fig. 1B). On the other hand, corticosterone was significantly modified by the different environmental treatments [F(7,100) = 5.85, P < 0.0001] (Fig. 1C). During standard housing, similar levels of corticosterone were found in CO and TS mice, and enrichment did not modify these values either in

Discussion

The present results confirm our previous findings [45]: (a) male TS mice performed worse than CO mice in the water maze test in any setting; (b) environmental enrichment did not modify cognitive performance in CO mice; (c) the performance was deteriorated in mice subjected to enrichment in large groups. Since the purpose of the present study was to understand the mechanisms accounting for this deteriorated cognition, it was hypothesized that TS mice could be more vulnerable to a potential

Acknowledgments

This work was supported by the Spanish Ministry of Education grant SAF-2002-02178 and The Jèrôme Lejeune Foundation. N.R. has a predoctoral scholarship from the Spanish Ministry of Education.

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