Persistent hyperactivity and distinctive strategy features in the Morris water maze in 3xTg-AD mice at advanced stages of disease.

Abstract

Search strategies in the Morris water maze provide useful insights on cognitive function that may reveal genotype differences not reflected by escape latency or distance. Its analysis is pointed out as a complementary tool to better define the phenotype and the effect of treatments in animal models in which both cognitive impairment and behavioral symptoms reproduce the clinical complexity of the Alzheimer's disease patient. Here, we studied the performance of 13-month-old male 3xTg-AD mice in 3 different paradigms (cue learning, place task, and probe trial) and as compared with age-matched nontransgenic mice. The quantitative analysis (escape latency, distance, and speed) showed that in all tasks, the cognitive performance of 3xTg-AD mice was interfered with by a persistent hyperactive pattern. Their worse cognitive function was revealed by the qualitative features of nonsearch behaviors (floating and circling) and search strategies (single and /mixed, goal directed and nongoal directed). The search pattern was based on mixed and nongoal-directed strategies, in contrast to the single and goal-directed strategies used by controls. In the place task, poor cognitive flexibility of 3xTg-AD mice was also shown in persistence of search in the cue-trained position and the need to correct the strategy to find the new location. Trials involving a naïve situation (first trial of the cue task) or the difficulty of a new task (first trial of the place task and the probe trial) were the most suitable to show the deficits. This qualitative analysis may also be useful in the assessment of preventive or therapeutical treatments.

Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging

“…Since 2006, our laboratory has been devoted to characterize the cognitive but also the non-cognitive symptoms (i.e., anxiety, phobias, bizarre behaviors, hyperactivity, disinhibition, apathy and motivation, persistence of behaviors, and diurnal rhythm disturbances) in the homozygous 3xTg-AD mice created by LaFerla ( Oddo et al, 2003 ). As we have consistently reported (e.g., Giménez-Llort et al, 2006 , 2008 , 2010 ; Baeta-Corral and Giménez-Llort, 2014 , 2015 ; Torres-Lista and Giménez-Llort, 2014 , 2015 ; Manuel et al, 2016 ), these animals show a noticeable BPSD-like profile. Recently, depressive-like profile has also been reported in the 3xTg-AD mice ( Romano et al, 2015 ), early symptoms bearing some resemblance to bipolar disorder have also been noticed ( Corrêa-Velloso et al, 2018 ), and the effects of preventive/therapeutical strategies on such BPSD-like symptoms have began to be studied ( García-Mesa et al, 2011 , 2012 ; Blázquez et al, 2014 ; Cañete et al, 2015 ; Torres-Lista and Giménez-Llort, 2015 ; Sabogal-Guáqueta et al, 2017 ).…”

“…The anxiogenic conditions that the MWM represents for mice were also reflected in the high level of floating observed in NTg animals and the sustained increase in the speed of 3xTg-AD mice. As we have extensively discussed in a precedent report’ ( Baeta-Corral and Giménez-Llort, 2015 ), this means that in this colony of 3xTg-AD mice, the MWM may probably not be specific to assess hippocampal-dependent cognitive deficits related to spatial memory, as in other models for AD (i.e., Arendash et al, 2009 ). In this mice model, the MWM may involve the assessment of cognition under anxiogenic conditions and therefore the measurement of emotional memory depending on limbic system.…”

“…Also, because in our hands 3xTg-AD mice showed a persistence of behaviors in the FST that interfered with the interpretation of the performances ( Torres-Lista and Giménez-Llort, 2014 , 2015 ). Instead, the presence of immobility (floating) was taken into account in all the trials in the maze (as described in Baeta-Corral and Giménez-Llort, 2015 ) and the “Cue learning with a visible platform” was a specific paradigm used to control lack of motivation as well as sensorimotor differences. Besides, the effect of caffeine on other variables such as exploration in the ACTs and more specifically the performance in the HB test for novelty seeking was among the studied behaviors as opposed to the expression of apathy/depressive symptoms.…”

“…Finally, the swim paths for each mouse in each trial of the cue learning task, place learning task, and probe trial were analyzed following the swimming strategies described by Janus (2004) and classified according to three criteria: the objective (non-search behaviors, namely floating and circling, vs. search strategies), the direction (goal-directed vs. non-goal-directed strategies), and the variety (single vs. mixed strategies) (see Baeta-Corral and Giménez-Llort, 2015 ).…”

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

“…The MWM has been frequently utilized to determine cognitive deficits in AD animal models (Bromley-Brits et al, 2011; Baeta-Corral and Gimenez-Llort, 2015), and it has been useful to study hippocampal-dependent learning including short- and long-term spatial memory. Indeed, mice with hippocampal lesions cannot perform the task.…”