title: Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice.
abstract: Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IP-derived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression- and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target.
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors: Federica
authors: F
authors: Klaus
authors: Viral Vector Facility, Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors: Jean-Charles
authors: JC
authors: Paterna
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors: Elisa
authors: E
authors: Marzorati
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors: Hannes
authors: H
authors: Sigrist
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors: Lea
authors: L
authors: Götze
authors: Severin
authors: S
authors: Schwendener
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors: Giorgio
authors: G
authors: Bergamini
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors: Elisabeth
authors: E
authors: Jehli
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors: Damiano
authors: D
authors: Azzinnari
authors: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors: René
authors: R
authors: Fuertig
authors: Institute of Experimental Immunology, Inflammation and Sickness Behaviour, University of Zurich, Switzerland.
authors: Adriano
authors: A
authors: Fontana
authors: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors: Erich
authors: E
authors: Seifritz
authors: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland. Electronic address: christopher.pryce@bli.uzh.ch.
authors: Christopher R
authors: CR
authors: Pryce
mesh_terms: D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal; D001932:Brain Neoplasms / Q000503:physiopathology* / Q000523:psychology*; D003214:Conditioning, Classical; D003863:Depression; D004660:Encephalitis / Q000503:physiopathology* / Q000523:psychology*; D005239:Fear; D055809:Illness Behavior; D008297:Male; D008568:Memory; D008810:Mice, Inbred C57BL; D009336:Necrosis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: AAV-vector; Anxiety; Anxiety disorders; Cytokine hypothesis; Depression; Fear learning-memory; Reward; Sickness; TNF