Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

BACKGROUND/OBJECTIVES: Nuclear peroxisome proliferator activated receptor-alpha (PPAR-alpha) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-alpha in mouse behavior. METHODS: To investigate the function of Ppar-alpha in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-alpha was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-alpha was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T+tf/J) exhibiting a high rate of repetitive behavior. RESULTS: An unexpected role for brain Ppar-alpha in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-alpha genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-alpha deficient mice. Importantly, we reveal that pharmacological PPAR-alpha agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T+tf/J mice. CONCLUSION: Our data indicate that Ppar-alpha is required for normal cognitive function and that pharmacological stimulation of PPAR-alpha improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.