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

Giuseppe D'Agostino, Claudia Cristiano, David J Lyons, Rita Citraro, Emilio Russo, Carmen Avagliano, Roberto Russo, Giuseppina Mattace Raso, Rosaria Meli, Giovambattista De Sarro, Lora K Heisler, Antonio Calignano

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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.

Original languageEnglish
Pages (from-to)528-536
Number of pages9
JournalMolecular Metabolism
Volume4
Issue number7
Early online date2 May 2015
DOIs
Publication statusPublished - Jul 2015

Fingerprint

PPAR alpha
Peroxisome Proliferator-Activated Receptors
Pharmacology
Cognition
Genetic Models
Phenotype
Risperidone
Ketamine
Dyslipidemias
Pharmaceutical Preparations
Psychotic Disorders
Antipsychotic Agents
Homeostasis
Lipids
Brain
Therapeutics

Keywords

  • lipids
  • nuclear receptor
  • ketamine
  • memory
  • neurodevelopmental disorders
  • stereotyped behavior

Cite this

D'Agostino, G., Cristiano, C., Lyons, D. J., Citraro, R., Russo, E., Avagliano, C., ... Calignano, A. (2015). Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice. Molecular Metabolism, 4(7), 528-536. https://doi.org/10.1016/j.molmet.2015.04.005

Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice. / D'Agostino, Giuseppe; Cristiano, Claudia; Lyons, David J; Citraro, Rita; Russo, Emilio; Avagliano, Carmen; Russo, Roberto; Raso, Giuseppina Mattace; Meli, Rosaria; De Sarro, Giovambattista; Heisler, Lora K; Calignano, Antonio.

In: Molecular Metabolism, Vol. 4, No. 7, 07.2015, p. 528-536.

Research output: Contribution to journalArticle

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 2015, 'Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice', Molecular Metabolism, vol. 4, no. 7, pp. 528-536. https://doi.org/10.1016/j.molmet.2015.04.005
D'Agostino, Giuseppe ; Cristiano, Claudia ; Lyons, David J ; Citraro, Rita ; Russo, Emilio ; Avagliano, Carmen ; Russo, Roberto ; Raso, Giuseppina Mattace ; Meli, Rosaria ; De Sarro, Giovambattista ; Heisler, Lora K ; Calignano, Antonio. / Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice. In: Molecular Metabolism. 2015 ; Vol. 4, No. 7. pp. 528-536.
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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.",
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note = "Acknowledgments We thank Luca Giordano, Giovanni Esposito and Angelo Russo for technical assistance and Dr. Livio Luongo (Second University of Naples–Italy) for critical discussions. This work was supported by a Grant PRIN from Ministry of Education, Universities and Research (MIUR), Italy, to A.C. and the Wellcome Trust (WT098012) to L.K.H. and BBSRC (BB/K001418/1) to L.K.H. and G.D’A. G.D’A. received partial supports from a “FORGIARE” post-doctoral fellowship cofounded by the Polo delle Scienze e Tecnologie per la Vita, University of Naples Federico II and Compagnia di San Paolo Foundation, Turin, Italy (2010–2012).",
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T1 - Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

AU - D'Agostino, Giuseppe

AU - Cristiano, Claudia

AU - Lyons, David J

AU - Citraro, Rita

AU - Russo, Emilio

AU - Avagliano, Carmen

AU - Russo, Roberto

AU - Raso, Giuseppina Mattace

AU - Meli, Rosaria

AU - De Sarro, Giovambattista

AU - Heisler, Lora K

AU - Calignano, Antonio

N1 - Acknowledgments We thank Luca Giordano, Giovanni Esposito and Angelo Russo for technical assistance and Dr. Livio Luongo (Second University of Naples–Italy) for critical discussions. This work was supported by a Grant PRIN from Ministry of Education, Universities and Research (MIUR), Italy, to A.C. and the Wellcome Trust (WT098012) to L.K.H. and BBSRC (BB/K001418/1) to L.K.H. and G.D’A. G.D’A. received partial supports from a “FORGIARE” post-doctoral fellowship cofounded by the Polo delle Scienze e Tecnologie per la Vita, University of Naples Federico II and Compagnia di San Paolo Foundation, Turin, Italy (2010–2012).

PY - 2015/7

Y1 - 2015/7

N2 - 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.

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KW - nuclear receptor

KW - ketamine

KW - memory

KW - neurodevelopmental disorders

KW - stereotyped behavior

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DO - 10.1016/j.molmet.2015.04.005

M3 - Article

VL - 4

SP - 528

EP - 536

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

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