The triple-transgenic mouse (3xTg_AD), harboring PS1M146V, APPswe,TauP301L human transgenes and mimicking many critical hallmarks of Alzheimer's Disease (AD), show a temporal profile and specific anatomical pattern that reproduces the neuropathological progression which occurs in the human AD brain. This mice model progressively develops memory deficits and behavioural and psychological symptoms of dementia (BPSD) at early ages, when no overt neuropathology is observed yet but intraneuronal amyloid Aβ-peptide (Aβ) has been described. The first aim of this thesis was to perform a behavioural screening of cognitive deficits and BPSD symptoms at several stages of development of these transgenic animals. We have assessed the basic sensorimotor abilities, neophobic responses and circadian rhythms of motor activity in 3xTgAD mice at young (2 months old), adult (4 and 6 months when only intraneuronal Aβ immunoreactivity has been described) and older ages (9, 12 and 15 months, where there are progressive and increased Aβ neuropathology and extracellular tangles of tau protein). The results indicate that, at all ages, 3xTgAD mice show signs of neophobia and baseline motor hypoactivity, whereas they show no evidence of sensorimotor problems. Likewise, we have characterized the behavioral phenotype of 3xTgAD mice at 4 months of age, including the assessment of cognitive processes as well as BPSD symptoms. Animals were tested for spatial learning and memory in the Morris water maze, while the non cognitive profile was characterized by measuring neophobia (“corner test” index measure), exploratory and emotional/anxiety-like behaviour (Open Field test), anxiety (dark-light box and plus-maze tests), exploration and novelty-seeking behaviors (Boissier’s 16 hole-board) and circadian spontaneus activity (activity cage and radial tunnel-maze tests). On the other hand, early postnatal handling (PH, tactile stimulation administered from postnatal days 1 to 21) is an early-life treatment known to produce profound and long-lasting behavioural and neurobiological effects. Emotionality, reactivity to stressors and exploratory behaviour as well as the functionality of several neurotransmitter systems can be enduringly altered by this procedure. The present study was also aimed at describing the long-lasting effects of PH on the behavioural profile (both cognitive and non-cognitive) of male and female 3xTgAD mice at early stages of the disease, i.e. at 4 months of age. The results obtained show that 3xTgAD mice displayed an impaired spatial learning capacity at 4 months of age as compared to controls. Likewise, we have found gender differences, with 3xTgAD males showing better spatial learning, less anxious behavior and higher levels of motor hyperactivity than 3xTgAD females. Moreover, PH treatment reduced the excessive hyperactivity observed in 3xTgAD males and attenuated anxiety in females. Remarcably, PH treatment improved the acquisition of spatial place learning in the Morris water maze and decreased (the excessive) swimming speed in 3xTgAD mice. Therefore, the results clearly indicate that postnatal handling may exert a preventive effect on both emotional and cognitive alterations which are characteristic of the 3xTgAD model of Alzheimer’s disease.
Efectos de la estimulación postnatal en el perfil cognitivo i emocional del modelo de ratón 3XtgAD para la enfermedad de Alzheimer
Cañete Ramírez, A. (Author). 30 Jun 2011
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis