Operant discrimination learning in 5xFAD mice: Early detection and longitudinal monitoring of cognitive impairment

"Valid preclinical modeling of the executive dysfunction deficits that characterize MCI is vital in developing next generation disease modifying therapies for AD. One of the few rodent paradigms suitable to reliably assess the early impairments in executive function and cognitive flexibility that characterize the human MCI condition is operant training. This technique is rarely used in dementia research, but offers four crucial advantages over the behavioral tasks that presently dominate preclinical AD studies:
1) it minimizes animal stress, 2) it is amenable to automation to improve experimental uniformity and reproducibility
3) it accommodates mice with motor deficits that are common in aged and late-stage AD models, and 4) it is readily adaptable to tease out nuanced behavioral changes across domains without requiring additional specialized equipment. We believe the wider uptake of such methods by the AD field has the potential to dramatically increase the translational utility of preclinical studies across the board. This collaboration across colleges will attempt to demonstrate that despite these downsides, the advantages of discrimination learning tasks for early-stage detection of cognitive deficits are well worth the investment. In so doing, we will test the central hypothesis that the highly characterized 5xFAD amyloid beta (Aβ) mouse model displays heretofore unreported executive function deficits far earlier in pathological progression than standard hippocampal learning tasks indicate. Crucially, we will map plasma biomarker changes (amyloid beta peptides and astrocyte-derived GFAP levels) to the cognitive trajectories of these mice."