Deficient learning and memory are well-established pathophysiologic features of depression, however, mechanisms of the enhanced learning of aversive experiences associated with this disorder are poorly understood. Currently, neurobiological mechanisms of enhanced retention of aversive memories during depression, and, in particular, their relation to neuroinflammation are unclear. As the association between major depressive disorder and inflammation has been recognized for some time, we aimed to address whether neuroinflammatory changes are involved in enhanced learning of adversity in a depressive state. To study this question, we used a recently described mouse model of enhanced contextual conditioning of aversive memories, the modified forced swim model (modFST). In this model, the classic two-day forced swim is followed by an additional delayed session on Day 5, where increased floating behaviour and upregulated glycogen synthase kinase-3 (GSK-3) are context-dependent. Here, increased time spent floating on Day 5, a parameter of enhanced learning of the adverse context, was accompanied by hypercorticosteronemia, increased gene expression of GSK-3α, GSK-3β, c-Fos, cyclooxygenase-1 (COX-1) and pro-inflammatory cytokines interleukin-1 beta (IL-1β), tumor necrosis factor (TNF), and elevated concentrations of protein carbonyl, a marker of oxidative stress, in the prefrontal cortex and hippocampus. There were significant correlations between cytokine levels and GSK-3β gene expression. Two-week administration of compounds with antidepressant properties, imipramine (7 mg/kg/day) or thiamine (vitamin B1; 200 mg/kg/day) ameliorated most of the modFST-induced changes. Thus, enhanced learning of adverse memories is associated with pro-inflammatory changes that should be considered for optimizing pharmacotherapy of depression associated with enhanced learning of aversive memories.

中文翻译：

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小鼠改良的游泳试验中不良记忆的增强条件与神经炎症改变有关-这种作用易受抗抑郁药的影响。

学习和记忆不足是抑郁症的公认病理生理特征，但是，与这种疾病相关的厌恶体验的增强学习机制却知之甚少。目前，尚不清楚抑郁症期间增强的厌恶记忆保持力的神经生物学机制，尤其是它们与神经炎症的关系。由于人们已经认识到主要的抑郁症和炎症之间的关联已有一段时间，因此我们旨在解决神经炎性变化是否与抑郁状态下逆境的增强学习有关。为了研究这个问题，我们使用了最近描述的增强厌恶记忆情境条件的小鼠模型，即改良的强迫游泳模型（modFST）。在这个模型中 经典的为期两天的强迫游泳，然后在第5天进行了额外的延迟训练，其中漂浮行为的增加和糖原合酶激酶3（GSK-3）的上调依赖于环境。在这里，在第5天漂浮的时间增加，这是增强对不良情境学习的一个参数，伴有高皮质激素血症，GSK-3α，GSK-3β，c-Fos，环氧合酶-1（COX-1）和前额叶皮层和海马中的促炎性细胞因子白介素-1β（IL-1β），肿瘤坏死因子（TNF）以及升高的羰基蛋白浓度（氧化应激的标志物）。细胞因子水平与GSK-3β基因表达之间存在显着相关性。两周服用具有抗抑郁特性的化合物丙咪嗪（7 mg / kg /天）或硫胺素（维生素B1；200 mg / kg /天）改善了大多数由modFST引起的变化。因此，不良记忆的增强学习与促炎性变化相关，应考虑优化与厌恶记忆的增强学习相关的抑郁症药物治疗。