National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2011 Aug 3;476(7361):458-61. doi: 10.1038/nature10287.
Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.
糖皮质激素是对压力体验的反应而释放的，它具有许多有益的体内平衡功能。然而，糖皮质激素的失调与认知障碍和抑郁疾病有关。在大脑中密集分布有应激激素受体的海马区，应激和糖皮质激素强烈抑制成年神经发生。神经发生减少与焦虑和抑郁的发病机制有关，但缺乏这一作用的直接证据。在这里，我们表明，海马体中产生的成年神经元是正常表达应激反应的内分泌和行为成分所必需的。使用转基因或辐射方法特异性地抑制成年神经发生，我们发现，与完整小鼠相比，在神经发生缺陷小鼠中，中等应激后糖皮质激素水平的恢复速度较慢，地塞米松对其的抑制作用也较弱，这与海马体在调节下丘脑-垂体-肾上腺（HPA）轴中的作用一致。与对照组相比，神经发生缺陷小鼠在急性应激后还表现出在新环境中食物回避增加、强迫游泳试验中行为绝望增加以及蔗糖偏好降低（一种快感缺失的测量方法）。这些发现确定了海马齿状回内的一小部分神经元，它们对 HPA 轴的海马负反馈控制至关重要，并支持成年神经发生在抑郁疾病中的直接作用。
