Fuchs Eberhard, Czéh Boldizsár, Kole Maarten H P, Michaelis Thomas, Lucassen Paul J
Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany.
Eur Neuropsychopharmacol. 2004 Dec;14 Suppl 5:S481-90. doi: 10.1016/j.euroneuro.2004.09.002.
Early hypotheses on the pathophysiology of major depression were based on aberrant intrasynaptic concentrations of mainly the neurotransmitters serotonin and norepinephrine. However, recent neuroimaging studies have demonstrated selective structural changes across various limbic and nonlimbic circuits in the brains of depressed patients. In addition, postmortem morphometric studies revealed decreased glial and neuron densities in selected brain structures supporting the idea that major depression may be related to impairments of structural plasticity. Stressful life events are among the major predisposing risk factors for developing depression. Using the chronic psychosocial stress paradigm in male tree shrews, an animal model with a high validity for the pathophysiology of depressive disorders, we found that 1 month of stress reduced the in vivo concentrations of the brain metabolites N-acetyl-aspartate, choline-containing compounds, and (phospho)-creatine, as well as the proliferation rate in the dentate gyrus and the hippocampal volume. Even though long-lasting social conflict does not lead to a loss of principal cells, the hippocampal changes were accompanied by modifications in the incidence of apoptosis. Notably, these suppressive effects of social conflict on hippocampal structure could be counteracted by treatment with the antidepressant tianeptine. These findings support current theories proposing that major depressive disorders may be associated with impairment of structural plasticity and neural cellular resilience, and that antidepressants may act by correcting this dysfunction.
关于重度抑郁症病理生理学的早期假说是基于主要神经递质血清素和去甲肾上腺素在突触内浓度异常。然而，最近的神经影像学研究表明，抑郁症患者大脑中各种边缘和非边缘回路存在选择性结构变化。此外，死后形态学研究显示，特定脑结构中的胶质细胞和神经元密度降低，这支持了重度抑郁症可能与结构可塑性受损有关的观点。生活应激事件是抑郁症发病的主要诱发风险因素之一。利用雄性树鼩的慢性心理社会应激模型（一种对抑郁症病理生理学具有高度有效性的动物模型），我们发现1个月的应激会降低大脑代谢物N-乙酰天门冬氨酸、含胆碱化合物和（磷酸）肌酸的体内浓度，以及齿状回的增殖率和海马体积。尽管长期的社会冲突不会导致主要细胞的丧失，但海马体的变化伴随着细胞凋亡发生率的改变。值得注意的是，社会冲突对海马结构的这些抑制作用可以通过使用抗抑郁药噻奈普汀进行治疗来抵消。这些发现支持了当前的理论，即重度抑郁症可能与结构可塑性和神经细胞恢复力受损有关，并且抗抑郁药可能通过纠正这种功能障碍起作用。
