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

doi:10.1016/j.molmet.2015.04.005

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 language	English
Pages (from-to)	528-536
Number of pages	9
Journal	Molecular Metabolism
Volume	4
Issue number	7
Early online date	2 May 2015
DOIs	https://doi.org/10.1016/j.molmet.2015.04.005
Publication status	Published - Jul 2015

Bibliographical 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).

Keywords

lipids
nuclear receptor
ketamine
memory
neurodevelopmental disorders
stereotyped behavior

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Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
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Cite this

D'Agostino, G., Cristiano, C., Lyons, D. J., Citraro, R., Russo, E., Avagliano, C., Russo, R., Raso, G. M., Meli, R., De Sarro, G., Heisler, L. K., & 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

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

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

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.",

keywords = "lipids, nuclear receptor, ketamine, memory, neurodevelopmental disorders, stereotyped behavior",

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

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{\textquoteright}A. G.D{\textquoteright}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).",

year = "2015",

month = jul,

doi = "10.1016/j.molmet.2015.04.005",

language = "English",

volume = "4",

pages = "528--536",

journal = "Molecular Metabolism",

issn = "2212-8778",

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number = "7",

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TY - JOUR

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.

AB - 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.

KW - lipids

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

C2 - 26137440

SN - 2212-8778

VL - 4

SP - 528

EP - 536

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 7

ER -

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

Abstract

Bibliographical note

Keywords

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