RESUMEN
Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders--such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder--these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes. Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety-like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behaviour.
Asunto(s)
Ansiedad/enzimología , Ansiedad/genética , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Glutatión Reductasa/metabolismo , Lactoilglutatión Liasa/metabolismo , Animales , Ansiedad/fisiopatología , Femenino , Regulación de la Expresión Génica , Glutatión Reductasa/genética , Lactoilglutatión Liasa/genética , Lentivirus/genética , Masculino , Ratones , Ratones Endogámicos , Estrés Oxidativo/genética , Fenotipo , Transducción GenéticaRESUMEN
BACKGROUND: Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J). RESULTS: The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response. CONCLUSION: We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases.
Asunto(s)
Envejecimiento/genética , Envejecimiento/fisiología , Secuencia de Aminoácidos , Animales , Encéfalo/citología , Quimiocina CCL19 , Quimiocinas CC/química , Quimiocinas CC/genética , Cromosomas de los Mamíferos/genética , Factor 1 de Crecimiento de Fibroblastos/genética , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Ratones Mutantes , Datos de Secuencia Molecular , Mutación/genética , Sistema Nervioso/metabolismo , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Retina/citología , Especificidad de la EspecieRESUMEN
Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)- and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm-/- cerebral cortex and a dramatic 78% decrease in Trp53-/- mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5-/- mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5-/- mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.