Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity.
Brain, Behavior, and Immunity. 2018-11-01; :
DOI: 10.1016/j.bbi.2018.11.316
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Fourrier C(1), Bosch-Bouju C(1), Boursereau R(1), Sauvant J(1), Aubert A(1), Capuron L(1), Ferreira G(1), Layé S(1), Castanon N(2).
Author information:
(1)INRA, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux,
France; Université de Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286,
33076 Bordeaux, France.
(2)INRA, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux,
France; Université de Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286,
33076 Bordeaux, France. Electronic address: .
Although the high prevalence of anxiety in obesity increasingly emerges as
significant risk factor for related severe health complications, the underlying
pathophysiological mechanisms remain poorly understood. Considering that chronic
inflammation is a key component of obesity and is well known to impact brain
function and emotional behavior, we hypothesized that it may similarly contribute
to the development of obesity-related anxiety. This hypothesis was experimentally
tested by measuring whether chronic food restriction, a procedure known to reduce
inflammation, or chronic anti-inflammatory treatment with ibuprofen improved
anxiety-like behavior and concomitantly decreased peripheral and/or hippocampal
inflammation characterizing a model of severe obesity, the db/db mice. In both
experiments, reduced anxiety-like behaviors in the open-field and/or elevated
plus-maze were selectively associated with decreased hippocampal tumor necrosis
factor-α (TNF-α) mRNA expression. Highlighting the causality of both events,
chronic central infusion of the TNF-α blocker etanercept was then shown to be
sufficient to improve anxiety-like behavior in db/db mice. Lastly, by measuring
the impact of ex-vivo etanercept on hippocampal synaptic processes underlying
anxiety-like behaviors, we showed that the anxiolytic effect of central TNF-α
blockade likely involved modulation of synaptic transmission within the ventral
hippocampus. Altogether, these results uphold the role of brain TNF-α in
mediating obesity-related anxiety and provide important clues about how it may
modulate brain function and behavior. They may therefore help to introduce novel
therapeutic strategies to reduce anxiety associated with inflammatory conditions.