title: Hippocampal structure and function are maintained despite severe innate peripheral inflammation.
abstract: Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1β, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1β and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1β and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Süß
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Liubov
authors.initials: L
authors.lastname: Kalinichenko
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Loskarn
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ettle
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany. Electronic address: johannes.schlachetzki@uk-erlangen.de.
authors.forename: Johannes C M
authors.initials: JC
authors.lastname: Schlachetzki
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology; D003866:Depressive Disorder / Q000209:etiology / Q000276:immunology*; D004660:Encephalitis / Q000209:etiology / Q000276:immunology*; D005260:Female; D006624:Hippocampus / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000276:immunology; D058953:Neural Stem Cells / Q000276:immunology; D055495:Neurogenesis / Q000276:immunology; D009474:Neurons / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha
keywords: Adult hippocampal neurogenesis; Anxiety; Depression; Locomotion; Neuroinflammation; Peripheral inflammation