title: Behavioral extremes of trait anxiety in mice are characterized by distinct metabolic profiles.
abstract: No comprehensive metabolic profile of trait anxiety is to date available. To identify metabolic biosignatures for different anxiety states, we compared mice selectively inbred for ∼ 40 generations for high (HAB), normal (NAB) or low (LAB) anxiety-related behavior. Using a mass spectrometry-based targeted metabolomics approach, we quantified the levels of 257 unique metabolites in the cingulate cortex and plasma of HAB, NAB and LAB mice. We then pinpointed affected molecular systems in anxiety-related behavior by an in silico pathway and network prediction analysis followed by validation of in silico predicted alterations with molecular assays. We found distinct metabolic profiles for different trait anxiety states and detected metabolites with altered levels both in cingulate cortex and plasma. Metabolomics data revealed common candidate biomarkers in cingulate cortex and plasma for anxiety traits and in silico pathway analysis implicated amino acid metabolism, pyruvate metabolism, oxidative stress and apoptosis in the regulation of anxiety-related behavior. We report characteristic biosignatures for trait anxiety states and provide a network map of pathways involved in anxiety-related behavior. Pharmacological targeting of these pathways will enable a mechanism-based approach for identifying novel therapeutic targets for anxiety disorders.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany. Electronic address: mfiliou@mpipsykl.mpg.de.
authors.forename: Michaela D
authors.initials: MD
authors.lastname: Filiou
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Nussbaumer
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany.
authors.forename: Larysa
authors.initials: L
authors.lastname: Teplytska
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D003198:Computer Simulation; D004195:Disease Models, Animal; D006179:Gyrus Cinguli / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D051379:Mice; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011237:Predictive Value of Tests; D040901:Proteomics; D019289:Pyruvic Acid / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000596:Amino Acids; D009249:NADP; D019289:Pyruvic Acid
keywords: Anxiety; HAB; In silico pathway prediction; Metabolomics; Molecular biosignatures