Assessment of Cognitive Phenotyping in Inbred, Genetically Modified Mice, and Transgenic Mouse Models of Alzheimer's Disease

Abstract

Genetically modified mouse models are being used predominantly to understand brain functions and diseases. Well-designed and controlled behavioral analyses of genetically modified mice have successfully led to the identification of gene functions, understanding of brain diseases, and development of treatments. Recently, complex and higher cognitive functions have been examined in mice with genetic mutations. Therefore, research strategies for cognitive phenotyping should be sophisticated and evolve to convey the exact meaning of the findings and provide robust translational tools for testing hypotheses and developing treatments. This review addresses issues of experimental design and discusses studies that have examined cognitive function using mouse strain differences, genetically modified mice, and transgenic mice for Alzheimer's disease.

Keywords: Fear conditioning; Hippocampus; Mice; Object recognition; Prefrontal cortex; Water maze.

Fig. 1. Procedure for a redundant place/cued version of the water maze task. The platform is visible on days 1, 2, 5, 6, 9, and 10 and hidden on days 3, 4, 7, 8, 11, and 12 (A). On the competition test (day 13), swim paths from a representative mouse that swam directly to the visible platform in its new location (left, i.e., cued responder) and a representative mouse that crossed the annulus where the escape platform had been during the previous 12 d of training (right, i.e., place responder) (B).

Fig. 2. Cued training (left) and place training (right) in the learning strategy-switching task (A). In a recent experiment [6], both C57BL/6 and DBA/2 mice received cued training for 4 days and then place training for 4 days. In the switched place training, C57BL/6 mice performed better than DBA/2 mice (B). A different cohort of C57BL/6 and DBA/2 mice received place training first, followed by cued training. In the switched cued training from place training, C57BL/6 mice also performed better than DBA/2 mice (C).

Fig. 3. Schematic diagram of delay (A), contextual (B), and trace (C) fear conditioning. In delay conditioning (A), the conditioned stimulus (CS), e.g., a tone precedes and overlaps with the unconditioned stimulus (US), e.g., foot shock. In contextual conditioning (B), the US is administered in a conditioning context. In trace fear conditioning (C), the CS and US are separated by a stimulus-free “trace interval” (dashed line).

Fig. 4. Schematic diagram of the novel object recognition task. A mouse is habituated to the arena (left) and familiarized with two identical objects. After a specific interval, a novel object is presented to a mouse.

Fig. 5. (A) Behavioral procedure for neophobia. The initial lemon-scented diet was given to mice after habituation to a plain liquid diet. The second lemon-scented diet was given 3 days later. (B) Suppression ratios of mice on exposure to the baseline liquid diet, when a non-nutritive flavor was added. Suppression ratio = Lemon-scented diet/(lemon-scented diet + baseline diet). Male C57BL/6 (n=10) and DBA/2 (n=10) mice exhibited suppressed consumption at the initial exposure and retained that experience later, as indicated by the absence of suppression relative to baseline. There was a significant difference in the consumption ratio between C57BL/6 and DBA/2 mice (F[1,18]=4.40, p<0.05). These data are from unpublished work in our laboratory.

Fig. 6. Schematic diagram of a Pavlovian-instrumental transfer. A mouse receives Pavlovian pairings of a conditioned stimulus, such as a light with a reward (A), and then instrumental conditioning with sucrose pellets (B). The ability of the CS to serve as a conditioned reinforcer is assessed (C).