Heightened Tameness and Accelerated Handling-Habituation in 3×Tg-AD Mice on a B6;129 Genetic Background

The triple transgenic mouse model of Alzheimer's disease (3×Tg-AD) has gained popularity in Alzheimer's research owing to the progressive development of both amyloid-β and tau pathologies in its brain. Prior handling-habituation, a necessary preparation procedure that reduces anxiety and stress in rodents, was seldom described in the literature involving these mice and needs to be addressed.

We sought to determine whether 3×Tg-AD mice differ from B6;129 genetic control mice in terms of tameness and prior habituation to handling.

We devised hand-staying and hand-boarding assays to evaluate tameness in 3×Tg-AD and B6;129 genetic control mice at 2.5, 7, and 11.5 months of age, representing cognitively pre-symptomatic, early symptomatic and advanced symptomatic stages of the disease, respectively. We monitored the progress of handling-habituation across 8-15 daily handling sessions and assessed the animal behaviors in elevated plus maze.

We found that 3×Tg-AD mice were markedly tamer than age-matched control mice at the baseline. Whereas it took 2-3 days for 3×Tg-AD mice to reach the criteria for full tameness, it took an average of 7-9 days for young genetic control mice to do so. Prior handling-habituation enhanced risk assessment and coping strategy in mice in elevated plus maze. Completely handling-habituated mice exhibited comparable anxiety indices in the maze regardless of genotype and age.

These findings collectively point to inherently heightened tameness and accelerated handling-habituation in 3×Tg-AD mice on a B6;129 genetic background. These traits should be carefully considered when behaviors are compared between 3×Tg-AD and the genetic control mice.