Aberrant Medial Prefrontal Cortex Activity and Flexible Behavior in the TgF344-AD Rat Model of Alzheimer's Disease.

Abstract

Executive dysfunction can precede the accumulation of canonical neuropathological markers and severe dementia in Alzheimer's disease (AD) patients often characterized by memory changes. Deficits in executive function including flexible behavior, i.e., the ability to shift behavior following negative consequences, are often mediated by the prefrontal cortex. However, it is unknown how medial prefrontal cortex activity is altered in behaving Tg-F344-AD rats, which exhibit age-dependent AD pathology and memory deficits. We tested the ability of in 6-7-month-old TgF344-AD rats to learn reward predictive cues and to shift behavior away from cues following outcome devaluation while recording mPFC neurons (wild-type, 10 males and 7 females; TgF344-AD, 8 males and 9 females). Rats were presented with two distinct cues as conditioned stimuli (CS+) predicting two distinct outcomes over learning. Then, a conditioned taste aversion to one outcome was induced, and rats were evaluated for their ability to avoid the CS+ associated with the devalued outcome. We found a loss of motivated behavior during learning and impaired flexible behavior in 6-7-month-old AD rats relative to controls. In addition, there was differential aberrant mPFC encoding of cue-outcome associations in AD rats during conditioning and following devaluation. AD rats showed fewer neurons during conditioning that encode both the cue and the outcome. Also, AD rats showed a greater proportion of neurons that exhibited an excited response to reward predictive cues following devaluation. Together, these data contribute to our understanding of alterations in mPFC that may underlie prodromal AD behavioral deficits to inform future treatments.