Impaired behavioral flexibility and coping strategy shifts in 5xFAD mice in the novel Destruction-Building Test.

Abstract

Introduction: The assessment of early ethological markers of neurodegeneration in Alzheimer's disease (AD) remains a pivotal task in preclinical research. This study evaluates the diagnostic potential of the "Destruction-Building Test" (DBT), a novel assay based on the innate manipulative behaviors of rodents-specifically material shredding and complex nest-building-as an early indicator of neurodegenerative changes.

Methods: Investigations were conducted on hemizygous 5xFAD transgenic mice and wild-type (WT) controls of both sexes at 15, 28, and 42 weeks of age. The protocol included a 24-h habituation phase with continuous actigraphy to assess spontaneous locomotor activity (SLA), followed by a 72-h phase of manipulative activity. Generalized Estimating Equations (GEE) were employed for statistical modeling.

Results: We observed a systemic reduction in manipulative activity in 5xFAD mice, which was most pronounced in females starting from 15 weeks of age. GEE modeling confirmed that genotype and sex were the primary determinants of shredding deficits (p < 10^-9). Furthermore, we identified a robust negative correlation between SLA during the initial adaptation phase and subsequent manipulative productivity in the DBT (p < 0.001); specifically, higher exploratory locomotion predicted less efficient shredding and nest-building. Transgenic animals demonstrated a pathological shift toward a proactive coping style characterized by unproductive hyperlocomotion and diminished manipulation, signaling impaired behavioral flexibility and cognitive rigidity.

Discussion: These findings suggest that the DBT is highly sensitive to early neurodegenerative manifestations before the onset of gross motor deficits.Its methodological simplicity and robust diagnostic value position the DBT as an effective tool for the longitudinal screening of cognitive status in AD mouse models.