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Tesi etd-11072015-004525

Thesis type
Tesi di laurea specialistica LC6
Developmental intellectual disability and aging: insights from murine model of Down syndrome
Corso di studi
relatore Prof. Cioni, Giovanni
Parole chiave
  • environmental enrichment
  • Down syndrome
  • Ts65Dn mouse
  • Alzheimer's disease
Data inizio appello
Riassunto analitico
Down syndrome (DS) represents the leading cause of intellectual disability (ID) of genetic origin and an important public health issue due to inability of affected individuals to live an independent life. At the moment DS is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. In addition, the biology of aging may be different in individuals with DS - there is an early-onset of Alzheimer’s disease (AD). Because of its complexity, many aspects of DS must be studied in both humans and animal models. In the present study, I focused on Ts65Dn mice, the best characterized and most widely used model of DS. Ts65Dn mice display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Recent findings in Ts65Dn mice have suggested that it is possible to rescue DS-related cognitive dysfunction in adulthood using environmental enrichment (EE), a paradigm of increased sensory-motor stimulation, throughout enhancement of neural plasticity. However, little is known about the therapeutic potential of EE in aged Ts65Dn mice and DS persons that display very complex cognitive phenotype in a form of AD dementia in the context of ID.
Aims of the thesis
The present study aims at providing initial evidence about the effects of long-term EE on cognitive performance in aged Ts65Dn mice. The principal objectives of the study were:
1. Investigation of the effects of long-term EE on spatial learning and memory in aged Ts65Dn and aged-matched control WT mice by use of Morris water maze test (MWM);
2. Investigation of the effects of long-term EE on short-term working memory in aged Ts65Dn and aged-matched control WT mice by use of Y maze test.
Materials and methods
Animals: In this study was used the transgenic line Ts65Dn that carries segmental trisomy in a form of Robertsonian translocation of Mmu16 to Mmu17 (1716). Segmental trisomy provokes male sterility, therefore female carriers of the 1716 chromosome are used to generate trisomic offspring by intercross with hybrid male mice. Real time PCR genotyping assay was used to genotype the progeny. Intervention: EE consisted in a complex rearing environment composed of motor, sensory, cognitive and social stimulation; mice were housed in large cages equipped with various objects that are completely replaced with others once per week. Behavioral assessment: the effects of intervention on spatial memory and learning was evaluated by MWM test, while the effects on short term working memory was evaluated by Y maze test. Statistics: statistical analysis were performed using SigmaStat Software.
Results and conclusions
My results demonstrated that long-term EE led to significant behavioral benefits in aged Ts65Dn such as facilitation of spatial learning and memory function in MWM and increased explorative behavior in Y maze. MWM test showed that long-term EE was able not only to prevent additional age-associated cognitive decline of already poor cognitive performance evident in young trisomic mice, but to completely rescue spatial learning in aged Ts65Dn mice. This is a first evidence that long-term EE may be successfully employed to reverse cognitive deficits in aged Ts65Dn mice. Given a non-invasive nature of EE paradigm, it would be of great clinical and social interest to perform novel studies that will explore the potential of increased environmental stimulation to ameliorate existing cognitive defects and to prevent additional cognitive decline in aging DS subjects.