Research reportBehavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome
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.
References (62)
- et al.
Neonatal stress and long-term modulation of GABA receptors in rat brain
Neurosci Lett
(1990) - et al.
Long-term changes induced by neonatal handling in the nociceptive threshold and body weight in mice
Physiol Behav
(1995) - et al.
Stress and cognition: are corticosteroids good or bad guys?
Trends Neurosci
(1999) - et al.
Spatial memory deficits in segmental trisomic Ts65Dn mice
Behav Brain Res
(1996) - et al.
Impaired cyclic AMP production in the hippocampus of a Down syndrome murine model
Dev Brain Res
(1996) - et al.
Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome
Brain Res
(1997) - et al.
A behavioral assessment of Ts65Dn mice: a putative Down syndrome model
Neurosci Lett
(1995) - et al.
Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome
Neurosci Lett
(1998) - et al.
On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models
Brain Res Revs
(2001) - et al.
Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions
Gene
(2003)
Effects of environmental enrichment on aggresive behavior, dominance hierarchies, and endocrine states in male DBA/2J mice
Physiol Behav
Hypothermia in mice tested in Morris water maze
Behav Brain Res
Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome
Neurosci Lett
Characterization of sensorimotor performance, reproductive and aggressive behaviors in segmental trisomic 16 (Ts65Dn) mice
Physiol Behav
Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice
Brain Res
Subchronic MK-801 treatment to juvenile rats attenuates environmental effects on adult spatial learning
Behav Brain Res
Effects of different forms of environmental enrichment on behavioural, endocrinological, and immunological parameters in male mice
Horm Behav
Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome
Behav Brain Res
Environmental influence on behaviour and nerve growth factor in the brain
Brain Res
Environmental enrichment from birth enhances visual acuity but not place learning in mice
Behav Brain Res
Factor analysis of spatiotemporal and ethological measures in the murine elevated plus maze of anxiety
Pharmacol Biochem Behav
Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome
Neuropharmacology
Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome
Neuropharmacology
Experimental parameters affecting the Morris water maze performance of a mouse model of Down syndrome
Behav Brain Res
Expression of neurotrophin-3 mRNA in the rat visual cortex and hippocampus is influenced by environmental conditions
Neurosci Lett
Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus
Behav Brain Res
Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse
Hum Mol Gen
Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome
J Comp Neurol
Chemical and anatomical plasticity in the brain
Science
Aggression: the testosterone-serotonin link
Isr Med Assoc J
Postnatal handling/maternal separation alters responses to startle and central benzodiazepine receptor level subtypes in adult rats
Soc Neurosci Abstr
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