Goal-directed action is transiently impaired in a hAPP-J20 mouse model of Alzheimer's disease.

Cognitive-behavioural testing in preclinical models of Alzheimer's disease has failed to capture deficits in goal-directed action control. Here we provide the first comprehensive investigation of goal-directed action in a transgenic mouse model of Alzheimer's disease. Specifically, we tested outcome devaluation performance in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press left and right levers for pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were pre-fed one of the outcomes to satiety and given a choice between levers. Devaluation performance was intact for 36-week-old wildtypes of both sexes, who responded more on the valued relative to the devalued lever (Valued > Devalued). By contrast, devaluation was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. After additional lever press training (i.e., 8 days lever pressing in total), devaluation was intact for all mice, demonstrating that the initial deficits were not a result of a non-specific impairment in reward processing, depression, or locomotor activity in J20 or aging mice. Follow up analyses revealed that microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial, but not later tests. Together, these data demonstrate that goal-directed action is initially impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 hippocampal region. Significance statement Treatments for Alzheimer's disease trialled in preclinical animal models have repeatedly failed to translate to the clinic. One potential reason for this could be that the cognitive-behavioural assays used in such models have been limited to one aspect of Alzheimer impairment: visuospatial memory. Here we demonstrate that male and female mice belonging to the transgenic hAPP-J20 mouse model also display consistent deficits in the initial acquisition of goal-directed action. This study therefore represents an important step towards the broader capture of Alzheimer-like cognitive deficits at a preclinical level which could improve translatability when used to more comprehensively test treatment efficacy prior to clinical trials.