Reward motivation and cognitive flexibility in tau null-mutation mice

Abstract

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau^-/-) and wild-type mice using progressive ratio and reversal learning tasks. Tau^-/- mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau^-/- mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.

Keywords: Operant conditioning; Progressive ratio; Reversal learning; Reward; Reward sensitivity; Tau knockout mice.