Academic journal article Cognitive, Affective and Behavioral Neuroscience

Environmental Enrichment Eliminates the Anxiety Phenotypes in a Triple Transgenic Mouse Model of Alzheimer's Disease

Academic journal article Cognitive, Affective and Behavioral Neuroscience

Environmental Enrichment Eliminates the Anxiety Phenotypes in a Triple Transgenic Mouse Model of Alzheimer's Disease

Article excerpt

Published online: 4 February 2014

© Psychonomic Society, Inc. 2014

Abstract Although the impacts of environmental enrichment (EE) in several genetic models of Alzheimer's disease (AD) have been documented, the focus has remained predominantly on cognition. Few have investigated the expression of emotional phenotypes that mimic the notable affective features in AD. Here, we studied the interaction between EE and the coexpression of three genetic risk factors (mutations) for AD. In a longitudinal design, 3×Tg-AD mutants and wild type controls were compared at 6-7 months and subsequently at 12-13 months of age. Under standard housing, phenotypes of heightened anxiety levels were identified in the 3×Tg-AD mice in the elevated plus maze and open-field tests. Such trait differences between genotypes were substantially diminished under EE housing, which was attributable to the anxiolytic impact of EE on the mutant mice as much as the anxiogenic impact of EE on the wild typemice. In contrast, the phenotypes in learned fear were not significantly modified by EE in the tests of Pavlovian freezing and conditioned active avoidance conducted at either age. Rearing under EE thus has uncovered a novel distinction between innate and acquired expressions of fear response in the 3×Tg-AD mouse model that might be relevant to the mental health management of AD.

Keywords Animal models · Anxiety · Emotion

Recent years have seen a number of studies investigating the impact of environmental/housing manipulations in genetic mouse models of Alzheimer's disease (AD; for reviews, see Nithianantharajah & Hannan, 2009, 2011). This interest is due to the relevance of gene-environment interactions in the etiopathology of AD, and the possible therapeutic value of environmental stimulation (Andel et al., 2005; Crowe, Andel, Pedersen, Johansson, & Gatz, 2003; Vespa, Gori, & Spazzafumo, 2002). Indeed, converging lines of evidence suggest that a stimulating lifestyle that engages physical exercise and intellectual and social activities can slow down the progress of the disease and attenuate the severity of the symptoms in AD patients (Butler, Ashford, & Snowdon, 1996; Katzman, 1993; Mortimer, Borenstein, Gosche, & Snowdon, 2005; Palleschi et al., 1996; Rovio et al., 2005; Vespa et al., 2002;Wilson et al., 2002). One common tool to translate and explore these findings in preclinical animal models is environmental enrichment (EE).

Under EE, mice or rats are exposed to multiple forms of enhanced stimulation, including motor, sensorial, cognitive, and social stimulation in their daily living (Hebb, 1947; Renner & Rosenzweig, 1987). EE is typically implemented by group-housing animals in large cages containing varying sets of toys, tunnels, and running wheels (Renner & Rosenzweig, 1987). Rearing under EE is known to induce marked neuroprotective effects and improve emotional and cognitive function in wild type animals (Diamond, 2001; Rosenzweig & Bennett, 1996; van Praag, Kempermann, & Gage, 2000; Will, Galani, Kelche, & Rosenzweig, 2004), especially when initiated early in life-typically from weaning (Kohl, 2002; Renner & Rosenzweig, 1987). These observations support the idea that environmental stimuli can critically modify the phenotypic expression of even highly inheritable traits (Pigliucci, 2001; Waddington, 1957). Such "phenotypic plasticity" would be particularly relevant to familial AD with identifiable genetic risk factors, and it can be studied in genetically modified mouse models bearing one or more of the relevant susceptibility genes or mutations.

Indeed, beneficial effects of EE on brain and behavior have been demonstrated in several genetic mouse models of AD (for reviews, see Nithianantharajah & Hannan, 2009, 2011). AD models aremainly based on single or combined mutations in genes encoding the amyloid precursor protein (APP) and the presenilins (PS1, PS2) (Gotz et al. …

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