Research report
Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome

https://doi.org/10.1016/S0166-4328(02)00026-8Get rights and content

Abstract

We have assessed the effects of enriched environment (EE) upon behavioral and cognitive performances of partially trisomic Ts65Dn (TS) mice and their control (CO) littermates. Enriched environment was applied to pups for 7 weeks after weaning. Circadian spontaneous activity (actimetry), exploratory behavior (hole board), activity in the open field and spatial memory (Morris Water Maze, repeated acquisition and cued paradigms) were analyzed in 86 female and 75 male mice, starting 15 days after completing enrichment. For each gender, mice were distributed in non-enriched and enriched control and trisomic groups. Enriched environment reduced in trisomic females and enhanced in trisomic males’ circadian activity. Exploratory behavior was increased by enrichment in all groups, regardless of gender or presence of trisomy. In the Morris Water Maze, a significant improvement of the spatial memory was observed in enriched-control females, but not in enriched-control male mice, as assessed by distances traveled. Performances in the four groups of control animals were also consistently and significantly better than those of matching trisomic mice. In the acquisition trials, enrichment improved performance in trisomic female animals, but deteriorated in trisomic male mice. In all groups, changes in escape latencies and distances induced by enrichment were accounted for by changes in the total time spent in the periphery of the pool, indicating changes in learning strategy. Working memory was the function more affected by enrichment. It is concluded that enriched environment induces behavioral and learning changes in trisomic mice, although gender plays a significant modulatory role.

Introduction

Early experience is known to alter both behavior and brain structure [23]. Environmental enrichment (EE) is associated with morphological, physiological and behavioral consequences. Morphological changes include increased cortical weight and thickness, alterations in cortical connectivity consisting of a larger number of synapses per neuron, lower neuronal density, increased dendritic branching and length, greater numbers of dendritic spines, increased size and number of synaptic junctions and increased neurogenesis in specific areas [17], [27], [29], [41], [57]. Indeed, many of these changes are consistent with enrichment-induced changes in the expression of genes involved in neuronal structure, synaptic signaling and plasticity [45] Facilitation of hippocampal responses, such as long-term synaptic potentiation and increases in protein kinase C, have also been reported [22], [44].

These morphological and physiological effects may account for the EE induced behavioral changes, including spontaneous and exploratory activity, enhanced perceptive abilities, better performance and more efficient learning, documented in various cognitive and behavioral tasks [2], [9], [11], [17], [32], [37], [47], [50], [51], [54], [58], [60], [61], [62], [63].

An important question is whether genetic or chromosomal anomalies severely affecting mechanisms underlying cerebral development, would compromise the ability of the animals to respond to environmental stimulation in terms of neural plasticity and behavior. Down syndrome (DS) is the most significant genetic cause of mental retardation. Positive short-term effects of early intervention for children with DS are well recognized, whereas long-term effects are less documented [19]. The possibility to replicate this approach in an animal model of DS offers the advantage of separately analyzing the many factors possibly involved in the EE stimulation. Comparative mapping between mice and humans has revealed that human chromosome 21 (HSA21) shares a large region of genetic homology with mouse chromosome 16 (MMU16). Currently, there are several murine models with segmental trisomy MMU16. The Ts(1716)65Dn (Ts65Dn) originally developed by Davisson et al. [6], includes most of the MMU16 region homologous to HSA21 (from App to the distal telomere), but lacks the remaining ≈25% of HSA21 genes. Ts65Dn mouse is the most accepted animal model for human trisomy 21 or Down syndrome [7], [14]. The animals show cognitive deficits in spatial learning as well as in working and long-term memory, hyperactivity, reduced attention levels and an altered response to novel environments [4], [8], [15], [16], [24], [31], [46] motor dysfunction [3] and reduced responsiveness to painful stimuli [39]. Neurochemical studies revealed brain abnormalities in the adenylyl cyclase and phospholipase C signaling pathways [12], [13], [48]. Irregularities in the cellularity of some regions of the hippocampus, a reduction of asymmetric synapses in the temporal cortex and a reduction of both internal granule layer and molecular layer of the cerebellum have been documented [1], [26], [33]. Electrophysiological studies have also shown decreased long-term potentiation and enhanced long-term depression in hippocampal slices [52], [53].

The present study was aimed at exploring the influence of post-weaning EE on behavioral performance and learning abilities of Ts65Dn mice compared with their control non-trisomic littermates, with special emphasis on working and reference memories. To date, most of the behavioral studies in this model have been performed in male mice; however, since gender plays a significant role in the response to enrichment [21], [30], [36], our study considered the influence of gender for Ts65Dn and control groups.

Section snippets

Animals

Mice were generated by repeated backcross of Ts65Dn females to C57BL/6Jei x C3H/HeSnJ (B6EiC3) F1 hybrid males. The parental generation was prepared in the research colony at The Jackson Laboratory and mating was performed at the Animal Facilities of the University of Cantabria. The euploid littermates of Ts65Dn served as controls. After weaning, the animals were separated by sex and were randomly assigned to and reared in either a standard non-enriched environment (NE) or an enriched

Actimetry

In male mice, all groups showed significant variation of circadian activity along the 24 h cycle (MANOVA ‘hour’: F(23,49)=21.22, P<0.001), but the level of variation differed depending on the group (MANOVA ‘hour×group’ F(69,153)=1.3, P<0.01). TS/EE mice showed hyperactivity compared to both CO groups and to TS/NE mice at several points of the light period (ANOVA ‘group’: 8th hour, F(3,74)=7.2, P<0.001; 9th hour, F(3,74)=2.7, P<0.05; 10th hour, F(3,74)=3.8, P<0.05) and the dark period (ANOVA

Discussion

Our results confirm that Ts65Dn mice show spatial learning difficulties and extend these findings to the female population. They also demonstrate that EE can modulate behavior and learning of these genetically disturbed mice in a gender-dependent manner. Our results emphasize the need to include gender in any discussion on this specific model.

Because of differences in speed, traveled distances in MWM were computed as the relevant measure. Learning was impaired in trisomic male and female mice

Acknowledgements

We thank Marı́a J. Rozas and Sara P. de Lastra for excellent technical assistance in running the experiments. The work was supported by grants from the Foundation ‘Marcelino Botı́n’, the Spanish Ministry of Education and Science (JF) (PB94-1063-C02-01, SAF99-0092-C02-02), FIS00/0795, CEC/BIOMED BMH4-CT98-3039 and National Institutes of Child Health and Human Development, contract HD73264 (MTD). CMC received a fellowship from Gobierno Vasco and Real Patronato de Minusvalı́as.

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