title: Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet.
abstract: An association between metabolic abnormalities, hypercholesterolemia and affective disorders is now well recognized. Less well understood are the molecular mechanisms, both in brain and in the periphery, that underpin this phenomenon. In addition to hepatic lipid accumulation and inflammation, C57BL/6J mice fed a high-cholesterol diet (0.2%) to induce non-alcoholic fatty liver disease (NAFLD), exhibited behavioral despair, anxiogenic changes, and hyperlocomotion under bright light. These abnormalities were accompanied by increased expression of transcript and protein for Toll-like receptor 4, a pathogen-associated molecular pattern (PAMP) receptor, in the prefrontal cortex and the liver. The behavioral changes and Tlr4 expression were reversed ten days after discontinuation of the high-cholesterol diet. Remarkably, the dietary fat content and body mass of experimental mice were unchanged, suggesting a specific role for cholesterol in the molecular and behavioral changes. Expression of Sert and Cox1 were unaltered. Together, our study has demonstrated for the first time that high consumption of cholesterol results in depression- and anxiety-like changes in C57BL/6J mice and that these changes are unexpectedly associated with the increased expression of TLR4, which suggests that TLR4 may have a distinct role in the CNS unrelated to pathogen recognition.
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK; Institute for Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal; Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Evans
authors.affiliation: Institute for Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal; Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands.
authors.forename: Joao
authors.initials: J
authors.lastname: Costa-Nunes
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnii Proesd 1, Chernogolovka, 142432 Moscow Region, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Bachurin
authors.affiliation: Division of Cardiology, University Hospital Magdeburg, Leipziger Strasse, 44, 39120 Magdeburg, Germany.
authors.forename: Naira
authors.initials: N
authors.lastname: Yeritsyan
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands.
authors.forename: Harry M W
authors.initials: HM
authors.lastname: Steinbusch
authors.affiliation: Department of Anatomy and Embryology, Maastricht University, Universiteitssingel 50, NL 6229 ER Maastricht, Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Eleonore Köhler
authors.affiliation: Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Fuechsleinstrasse 15, 97080 Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK. Electronic address: daniel.anthony@pharm.ox.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D003863:Depression / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002784:Cholesterol
keywords: Affective disorders; Anxiety; CNS; Cholesterol; Depression; Hepatosteatosis; Impulsivity; Mouse; Toll-like receptor four (Tlr4); Western diet