Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity
Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity
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DOI：
10.1016/j.bbi.2018.11.316
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发表时间：
2019-03-01
影响因子：
15.1
通讯作者：
Castanon, Nathalie
中科院分区：
文献类型：
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作者：
Fourrier, Celia;Bosch-Bouju, Clementine;Castanon, Nathalie
尽管肥胖中焦虑的高患病率越来越成为相关严重健康并发症的重要风险因素，但其潜在的病理生理机制仍然知之甚少。考虑到慢性炎症是肥胖的关键组成部分，并且众所周知会影响大脑功能和情绪行为，我们假设它可能同样有助于肥胖相关焦虑的发展。通过测量慢性食物限制（一种已知减少炎症的程序）或用布洛芬进行的慢性抗炎治疗是否改善焦虑样行为并伴随减少表征严重肥胖模型（db/db小鼠）的外周和/或海马炎症，来实验性地测试该假设。在这两个实验中，减少焦虑样行为在开放领域和/或高架十字迷宫选择性地与海马肿瘤坏死因子-α（TNF-α）mRNA表达减少。强调了这两种事件的因果关系，然后显示TNF-α阻滞剂依那西普的慢性中枢输注足以改善db/db小鼠的焦虑样行为。最后，通过测量离体依那西普对焦虑样行为背后的海马突触过程的影响，我们表明中枢TNF-α阻滞的抗焦虑作用可能涉及腹侧海马内突触传递的调节。总之，这些结果支持脑TNF-α在介导肥胖相关焦虑中的作用，并为它如何调节脑功能和行为提供了重要线索。因此，它们可能有助于引入新的治疗策略，以减少与炎症相关的焦虑。
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-alpha (TNF-alpha) mRNA expression. Highlighting the causality of both events, chronic central infusion of the TNF-alpha 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-alpha blockade likely involved modulation of synaptic transmission within the ventral hippocampus. Altogether, these results uphold the role of brain TNF-alpha 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.