TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting

Biol Psychiatry. 2006 May 1;59(9):775-85. doi: 10.1016/j.biopsych.2005.10.013. Epub 2006 Feb 3.


Background: Increased serum levels of TNFalpha and other pro-inflammatory cytokines have been found in patients with major depression and several other psychiatric conditions. In rodents, these cytokines produce symptoms commonly referred to as "sickness behavior." Some of these, including reduced feeding and decreased social and exploratory behavior, are reminiscent of those seen in depressed patients. Interpretation of these effects is complicated by the malaise caused by acute injections of pro-inflammatory cytokines, however. Thus, it is unclear whether cytokines are involved in the etiology of depressive symptoms.

Methods: We used a panel of behavioral assays to assess TNFR1(-/-) and TNFR2(-/-) mice for anxiety and depression-like behaviors.

Results: We show that deletion of either TNFR1 or TNFR2 leads to an antidepressant-like response in the forced swim test and that mice lacking TNFR2 demonstrate a hedonic response in a sucrose drinking test compared with wildtype littermates. In addition, deletion of TNFR1 leads to decreased fear conditioning. There were no differences in behavior in anxiety tests for either null mutant.

Conclusions: These results are consistent with the hypothesis that TNFalpha can induce depression-like symptoms even in the absence of malaise and demonstrate that both receptor subtypes can be involved in this response.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anxiety / physiopathology*
  • Behavior, Animal / physiology
  • Conditioning, Psychological
  • Depression / physiopathology*
  • Disease Models, Animal
  • Drinking Behavior / physiology
  • Exploratory Behavior / physiology
  • Fear
  • Gene Expression / physiology
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • RNA, Messenger / metabolism
  • Reaction Time / physiology
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Signal Transduction / physiology*
  • Sucrose
  • Swimming / physiology
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha / physiology*


  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • recombinant human tumor necrosis factor-binding protein-1
  • Sucrose