Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.
Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.
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过氧化物酶体增殖物激活的受体α在小鼠的行为重复和认知灵活性中起着至关重要的作用。
DOI：
10.1016/j.molmet.2015.04.005
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发表时间：
2015-07
影响因子：
8.1
通讯作者：
Calignano A
中科院分区：
文献类型：
--
作者：
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
核过氧化物酶体增殖物激活受体-α（PPAR-α）在脂质稳态调节中起着重要作用，是治疗血脂异常药物的靶点。然而，关于PPAR-α在小鼠行为中的作用知之甚少。为了研究Ppar-α在认知功能中的功能，结合神经解剖学、生物化学和药理学操作，对具有Ppar-α靶向遗传破坏的小鼠进行行为表型分析。使用精神病药理学模型和表现出高重复行为率的遗传模型（BTBR T + tf/J）在小鼠中探索了PPAR-α的治疗利用性。揭示了脑Ppar-α在调节小鼠认知行为中的意想不到的作用。具体而言，我们观察到Ppar-α基因扰动促进皮质和海马区域的重新布线，以及对拟精神药物的认知能力、持续和迟钝反应的行为表型。此外，我们证明抗精神病药和自闭症谱系障碍（ASD）药物利培酮可以改善Ppar-α缺陷小鼠的行为特征。重要的是，我们发现，在BTBR T + tf/J小鼠中，药理学PPAR-α激动剂治疗可改善氯胺酮诱导的行为障碍和重复行为的药理学模型中的行为。我们的数据表明，Ppar-α是正常认知功能所必需的，并且在小鼠认知功能受损的药理学和遗传学模型中，对PPAR-α的药理学刺激可改善认知功能。因此，这些结果揭示了目前人类使用的一类药物的不可预见的治疗应用。脂质核受体PPAR-α是小鼠正常认知功能所必需的。Ppar-α基因消除促进小鼠的重复行为和认知能力。药物刺激PPAR-α可改善认知受损和重复行为增强模型的行为。我们的研究结果表明，Ppar-α可能是行为和代谢功能障碍之间的共同点。
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. 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. 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. 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. The lipid nuclear receptor PPAR-α is required for normal cognitive function in mice. Genetic ablation of Ppar-α promotes repetitive behavior and cognitive inflexibility in mice. Pharmacological stimulation of PPAR-α improves behaviors in models of impaired cognition and enhanced repetitive behavior. Our findings suggest Ppar-α as a possible point of commonality between behavioral and metabolic dysfunctions.
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影响因子：
3.7
作者：
Hakami T;Jones NC;Tolmacheva EA;Gaudias J;Chaumont J;Salzberg M;O'Brien TJ;Pinault D
通讯作者：
Pinault D
精神分裂症的皮质性白蛋白中间神经元和认知功能障碍。
影响因子：
15.9
作者：
Lewis DA;Curley AA;Glausier JR;Volk DW
通讯作者：
Volk DW
DOI：
10.1073/pnas.0308455101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Jackson, ME;Homayoun, H;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric
DOI：
10.1161/01.atv.0000163844.07815.c4
发表时间：
2005-06-01
影响因子：
8.7
作者：
Arakawa, R;Tamehiro, N;Yokoyama, S
通讯作者：
Yokoyama, S