Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice
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.
“In rodents, Ppar-α has been linked to brain dopamine function, a neurotransmitter system that is a target of some antipsychotic and autism spectrum disorder (ASD) medications. Specifically, Ppar-α activation improves antipsychotic medication adverse event oral tardive dyskinesia and indirectly reduces the activity of dopamine cells in the ventral tegmental area in rodents. In humans, dyslipidemia is more prevalent in individuals with schizophrenia and ASD compared to the general population.
…genetic inactivation of Ppar-α resembles a behavioral and cognitive phenotype consistent with preclinical models of schizophrenia and ASD. In an effort to elucidate the mechanism through which this phenotype is mediated, we analyzed the brain. We observed that the genetic prevention of Ppar-α activity produced a reduction in cortical PV + GABAergic interneurons, consistent with post-mortem analyses of brains from patients with schizophrenia. We also report that the behavioral profile of Ppar-α null mice was improved with antipsychotic risperidone treatment. Thus, Ppar-α deficient mice may represent a new preclinical model to investigate the etiology and/or treatment of schizophrenia. The behavioral profile of Ppar-α null mice also shows similarities with ASD mouse model BTBR, which displayed an improved repetitive behavior with PPAR-α agonist treatment. Furthermore, risperidone is also used to alleviate hyperactivity, self-injurious, and repetitive behavior symptoms in humans suffering with ASD. Together, these results highlight PPAR-α as a potential point of commonality between schizophrenia and ASD worthy of further investigation.
Considering that repetitive behaviors can arise from a disruption in the direct cortico-striatal circuit, it is possible that PPAR-α plays an instrumental role in the organization and orchestration of PV + interneuron-pyramidal neuron cortical microcircuitry, and the absence of this regulation contributes to a net increase in cortical firing and output onto striatal structures. Supporting this possibility, GABAergic interneurons are crucial for synchronization of network activity, Ppar-α −/− mice exhibit abnormal EEG waves, and Ppar-α −/− mice are resistant to the behavioral disinhibition caused by the administration of NMDA receptor antagonists, which inhibit the activity of cortical PV + interneurons.
Given our observation that PPAR-α agonist treatment improves behavior in a pharmacological model of psychosis (ketamine) and a mouse model that displays face validity for ASD (BTBR), our research suggests that patients with schizophrenia and ASD co-prescribed fibrates to improve dyslipidemia may show a greater benefit in cognitive symptom amelioration. This possibility warrants further investigation in patient populations. Moreover, it is possible that at least a subset of these patients may receive direct therapeutic benefit from fibrates. If this were the case, it would have the added benefit of overcoming the metabolic disturbance associated with many current antipsychotic medications. Of interest, loss of function of Ppar-α results in middle age-onset obesity/weight gain in mice. Thus, increasing the activity of PPAR-α with compounds such as fibrates in patients may serve a further metabolic-protective role.
In conclusion, our findings disclose a previously unknown role for Ppar-α in cognitive function in mice. In addition to highlighting a neurological phenotype resulting from the loss of function of Ppar-α, our findings also suggest that this receptor may represent a target for the pharmacological amelioration of neurological conditions associated with behavioral perseveration/repetition. This is a particularly attractive prospect given that naturally occurring and synthetic PPAR-α agonists are currently used in clinical practice.”
Recent research has revealed that metabolic syndrome may be linked to sensory gating deficit in patients with schizophrenia and that the relationship between neurocognitive function and sensory gating deficits could be affected by the metabolic status of the patients . Similarly, medical treatment of certain components of the metabolic syndrome could affect cognitive performance in patients with schizophrenia . Weinstein et al.  recently found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism. Labouesse et al.  found that chronic consumption of a high-fat diet impairs sensorimotor gating in mice and this impairment was related to neural circuitry abnormalities, in particular to the striatal dopaminergic circuit: “It has been suggested that metabolic syndrome could affect the integrity of striatal dopaminergic circuits through the effect of metabolic circulating factors such as glucose, insulin or leptin”
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. PPAR-α acts as a key nutritional and environmental sensor for metabolic adaptation 
Natural ligands such as PUFAs are provided by the diet (linoleic, α-linolenic, γ-linolenic, and arachidonic acids) and bind to PPAR-α at physiologic concentrations
The beneficial effects of fish oil are thought to be, in part, mediated by activation of the nuclear receptor PPAR-α by omega-3 polyunsaturated fatty acids and the resulting upregulation of lipid catabolism 
It is well-known that dietary PUFAs have effects on diverse biological processes such as insulin action, cardiovascular function, neural development, and immune function, some of them mediated via PPARα.
Other natural compounds such as polyphenols have been described as ligands of PPAR-α: resveratrol, a natural polyphenol found in grapes, peanuts, and berries, and some of its derivatives and analogs, activate PPAR-α, resulting in brain protection against stroke. Genistein, another polyphenol that is the main soy isoflavone, induced the expression of PPAR-α at both messenger RNA (mRNA) and protein levels and enhanced expression of genes involved in fatty acid catabolism through activation of PPAR-α. Additional PPAR-α ligands from diet with hypolipidemic activity have been reported, such as the natural carotenoid abundant in seafood, astaxanthin, and the active compound extracted from the tomato, 9-oxo-10(E),12(E)-octadecadienoic acid. It has been demonstrated that phytanic acid, a branched-chain fatty acid generated from phytol present in dairy products, is also a natural ligand of PPAR-α.
Linalool is another orally active PPAR-α agonist 
Intriguingly, PPAR-α activation may stimulate allopregnanolone synthesis 
A recent study  found that autistic children exhibit decreased levels of essential fatty acids in red blood cells and increased levels of PUFA-derived metabolites such as prostaglandin E2.