Motivational drive influences motor and cerebellar alterations in the triple transgenic Alzheimer’s disease model

Abstract

Abstract Alzheimer’s disease (AD) is accompanied by early motor alterations, yet the contribution of motivational state and testing history to these changes remains poorly understood. We examined locomotor, fine-motor, and molecular profiles in 6–8-month-old male 3xTg-AD mice across separate cohorts. 3xTg-AD mice displayed reduced locomotion in the open field test, but this hypolocomotion was less evident in reward-driven contexts (such as single pellet reaching test, radial arm maze test, staircase test), where animals showed greater task engagement and, in several fine-motor readouts, higher goal-directed activity—consistent with context-dependent performance modulation rather than improved motor capacity. Muscle strength was reduced, whereas motor coordination remained intact. Myostatin–follistatin expression in the gastrocnemius muscle did not differ between genotypes and joint morphology appears preserved even after repeated test exposure, which can also be considered training. In contrast, the cerebellum exhibited elevated COXIV and pro-apoptotic markers (BAX, cleaved CASP3) in 3xTg-AD mice, while repeated test exposure was associated with a shift in apoptotic signaling toward an anti-apoptotic profile (Bcl-2 and pro-Casp3). Together, these findings point to early cerebellar vulnerability and highlight that motivational context and repeated task exposure influence behavioral outcomes in AD models.