Iwata Masaaki, Ishida Hisahito, Kaneko Koichi, Shirayama Yukihiko
Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Japan.
Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan.
Pharmacol Biochem Behav. 2016 Nov-Dec;150-151:138-146. doi: 10.1016/j.pbb.2016.10.005. Epub 2016 Oct 18.
An accumulating body of evidence has demonstrated that inflammation is associated with the pathology of depression. We recently found that psychological stress induces inflammation in the hippocampus of the rat brain through the inflammasome, a component of the innate immune system. Microglia, the resident macrophages in the brain, play a central role in the innate immune system and express inflammasomes; thus, we hypothesized that hippocampal microglia would be key mediators in the development of depression via stress-induced inflammation. To test this hypothesis and to determine how antidepressants modulate microglial function, we used immunohistochemistry to examine the morphological changes that occur in the hippocampal microglia of rats exposed to the learned helplessness (LH) paradigm. We noted significantly increased numbers of activated microglia in the granule cell layer, hilus, CA1, and CA3 regions of the hippocampi of LH rats. Conversely, administering imipramine to LH rats for 7days produced a significant decrease in the number of activated microglia in the hilus, but not in the other examined regions. Nonetheless, there were no significant differences in the combined number of activated and non-activated microglia either in LH or LH+imipramine rats relative to control rats. In addition, treating the naïve rats with imipramine or fluvoxamine produced no discernible microglial changes. These data suggest that stress activates hippocampal microglia, while certain antidepressants decrease the number of activated microglia in the hilus, but not in other hippocampal regions. Therefore, the hilus represents a candidate target region for the antidepressant imipramine.
越来越多的证据表明，炎症与抑郁症的病理过程有关。我们最近发现，心理应激通过炎性小体（先天免疫系统的一个组成部分）在大鼠脑海马体中诱导炎症。小胶质细胞是大脑中的常驻巨噬细胞，在先天免疫系统中起核心作用并表达炎性小体；因此，我们推测海马体小胶质细胞可能是应激诱导的炎症导致抑郁症发生过程中的关键介质。为了验证这一假设并确定抗抑郁药如何调节小胶质细胞功能，我们使用免疫组织化学方法检查了暴露于习得性无助（LH）范式的大鼠海马体小胶质细胞中发生的形态变化。我们注意到，LH大鼠海马体颗粒细胞层、齿状回、CA1和CA3区域中活化小胶质细胞的数量显著增加。相反，给LH大鼠服用丙咪嗪7天，齿状回中活化小胶质细胞的数量显著减少，但在其他检查区域没有减少。尽管如此，LH大鼠或LH +丙咪嗪大鼠中活化和未活化小胶质细胞的总数与对照大鼠相比没有显著差异。此外，用丙咪嗪或氟伏沙明治疗未处理的大鼠没有产生明显的小胶质细胞变化。这些数据表明，应激会激活海马体小胶质细胞，而某些抗抑郁药会减少齿状回中活化小胶质细胞的数量，但不会减少其他海马体区域的数量。因此，齿状回是抗抑郁药丙咪嗪的一个候选靶区。
