Joëls Marian, Karst Henk, Alfarez Deborah, Heine Vivi M, Qin Yongjun, van Riel Els, Verkuyl Martin, Lucassen Paul J, Krugers Harm J
SILS-CNS, University of Amsterdam, The Netherlands.
Stress. 2004 Dec;7(4):221-31. doi: 10.1080/10253890500070005.
It has become increasingly clear that the increase in corticosteroid levels, e.g. after a brief stressor induce molecular and cellular changes in brain, including the hippocampal formation. These effects eventually result in behavioral adaptation. Prolonged exposure to stress, though, may lead to mal-adaptation and even be a risk factor for diseases like major depression in genetically predisposed individuals. We conducted a series of experiments where changes in brain function were examined after 3 weeks of unpredictable stress. After unpredictable stress, inhibitory input to neurons involved in the hypothalamus-pituitary-adrenal (HPA) axis regulation was suppressed, which may dysregulate the axis and lead to overexposure of the brain to glucocorticoids. Furthermore, glutamate transmission in the dentate gyrus (DG) was enhanced, possibly through transcriptional regulation of receptor subunits. Combined with enhanced calcium channel expression this could increase vulnerability to cell death. Neurogenesis and apoptosis in the dentate were diminished. Synaptic plasticity was suppressed both in the dentate and CA1 area. Collectively, these effects may give rise to deficits in memory formation. Finally, we observed reduced responses to serotonin in the CA1 area, which could contribute to the onset of symptoms of depression in predisposed individuals. All of these endpoints provide potential targets for novel treatment strategies of stress-related brain disorders.
越来越明显的是，皮质类固醇水平的升高，例如在短暂应激源作用后，会在大脑中引发分子和细胞变化，包括海马结构。这些效应最终会导致行为适应。然而，长期暴露于应激可能会导致适应不良，甚至成为遗传易感性个体患重度抑郁症等疾病的危险因素。我们进行了一系列实验，在不可预测的应激3周后检查大脑功能的变化。在不可预测的应激后，参与下丘脑-垂体-肾上腺（HPA）轴调节的神经元的抑制性输入受到抑制，这可能会使该轴失调，并导致大脑过度暴露于糖皮质激素。此外，齿状回（DG）中的谷氨酸传递增强，可能是通过受体亚基的转录调控实现的。与增强的钙通道表达相结合，这可能会增加细胞死亡的易感性。齿状回中的神经发生和细胞凋亡减少。齿状回和CA1区的突触可塑性均受到抑制。总体而言，这些效应可能会导致记忆形成缺陷。最后，我们观察到CA1区对血清素的反应降低，这可能会导致易感个体出现抑郁症状。所有这些终点都为应激相关脑疾病的新型治疗策略提供了潜在靶点。
