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

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

Bottom Line: Specifically, we observed that Ppar-α 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-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) 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-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α 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-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α 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-α deficient mice. Importantly, we reveal that pharmacological PPAR-α 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-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α 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.

No MeSH data available.


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Mentions: Mice were first tested for short-term memory through the presentation of a novel object 10 min after the sampling phase (Figure 1A). During the sampling phase of the object recognition test, both wild type and Ppar-α −/− mice interacted equally with the two objects. During the short-term test, wild type mice showed a preference for the novel object, whereas Ppar-α −/− mice clearly preferred the familiar object (Figure 1A). This observation suggests a conservative behavior of mice lacking Ppar-α, and we interpreted the preference for the familiar object during the object recognition task as indicative of a repetitive/perseverative behavioral trait. To further explore this repetitive/perseverative phenotype, mice were assessed in a marble burying test, wherein mice are scored for the number of marbles they bury from the top of the bedding as an index for repetitive/perseverative behavior and compulsion [12]. We observed that Ppar-α −/− mice buried significantly more marbles than wild type littermates (Figure 1B), indicative of greater repetitive/perseverative behavior.


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

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481424&req=5

Mentions: Mice were first tested for short-term memory through the presentation of a novel object 10 min after the sampling phase (Figure 1A). During the sampling phase of the object recognition test, both wild type and Ppar-α −/− mice interacted equally with the two objects. During the short-term test, wild type mice showed a preference for the novel object, whereas Ppar-α −/− mice clearly preferred the familiar object (Figure 1A). This observation suggests a conservative behavior of mice lacking Ppar-α, and we interpreted the preference for the familiar object during the object recognition task as indicative of a repetitive/perseverative behavioral trait. To further explore this repetitive/perseverative phenotype, mice were assessed in a marble burying test, wherein mice are scored for the number of marbles they bury from the top of the bedding as an index for repetitive/perseverative behavior and compulsion [12]. We observed that Ppar-α −/− mice buried significantly more marbles than wild type littermates (Figure 1B), indicative of greater repetitive/perseverative behavior.

Bottom Line: Specifically, we observed that Ppar-α 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-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) 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-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α 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-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α 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-α deficient mice. Importantly, we reveal that pharmacological PPAR-α 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-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α 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.

No MeSH data available.


Related in: MedlinePlus