Genetic context and aging influence anxiety‐like behavior in diverse mouse models of Alzheimer’s disease

Abstract

AbstractBackgroundMany neuropsychiatric symptoms have been observed in humans with Alzheimer’s disease (AD). Significant changes in anxiety, depression, agitation, and apathy are present in AD patients relative to age‐matched controls, often occurring prior to the onset of cognitive deficits.MethodHere, we used the elevated plus maze (EPM) to examine anxiety‐like behavior in our AD‐BXD genetic reference panel to determine if sex, age (6 and 14m), or genetic background (28 BXD strains) influence anxiety in 5XFAD carrier (AD‐BXD) and non‐carrier (Ntg‐BXD) mice.ResultAt 6m of age, AD‐BXD strains spent significantly more time in the open arms (anxiolytic) compared to Ntg‐BXD controls, despite no differences in cognitive abilities (presymptomatic). The effect of the 5XFAD transgene on time spent in the open arms was exacerbated with aging, 14m AD‐BXD strains spent significantly more time in the open arms compared to both 6m 5XFAD carriers and non‐transgenic mice at either age. We also found a significant main effect of background strain and a strain by genotype interaction; indicating that the degree to which the transgene increased the time spent in open arms was dependent on individual genetic context. Interestingly, the anxiolytic response in these mice was mirrored by a decrease in locomotor activity (distance traveled).ConclusionContrary to increased anxiety described in human AD patients, we observed a decrease in anxiety‐like behaviors in the AD‐BXDs that exacerbated by age. However, circadian influence on anxiety may limit the translational relevance of this data set, especially considering the impact of strain, age, and genotype on locomotor activity. Ongoing work will investigate non‐anxiety‐like behavior in the EPM (risk‐taking), circadian‐dependent (i.e. morning vs. evening) changes in anxiety‐like behaviors, and gene expression in the hypothalamus as a function of anxiety‐like behavior.