Wong Edmund Y H, Herbert Joe
Department of Anatomy, University of Cambridge Downing Street, Cambridge CB2 3DY, UK.
Eur J Neurosci. 2005 Aug;22(4):785-92. doi: 10.1111/j.1460-9568.2005.04277.x.
New neurons are produced continually in the dentate gyrus of the hippocampus. Numerous factors modulate the rate of neuron production. One of the most important is the adrenal-derived corticoids. Raised levels of corticoids suppress proliferation of progenitor cells, while removal of corticoids by adrenalectomy reverses this. The exact mechanisms by which corticoids mediate such regulation are unknown, but corticoids are believed to act through the receptors for mineralocorticoids (MR) and glucocorticoids (GR). Previous reports regarding the roles of these receptors in regulating cell proliferation came to contrasting conclusions. Here we use both agonists and antagonists to these receptors in adult male rats to investigate and clarify their roles. Blockade of MR with spironolactone in adrenalectomised male rats implanted with a corticosterone pellet to reproduce basal levels enhanced proliferation, whereas treatment with the GR antagonist mifepristone had no effect. However, mifepristone reversed the suppressive effect of additional corticosterone in intact rats. Both aldosterone and RU362, agonists of MR and GR, respectively, reduced proliferation in adrenalectomised rats, and combined treatment with both agonists had an additional suppressive action. These results clearly show that occupancies of both receptors act in the same direction on progenitor proliferation. The existence of two receptors with different affinities for corticoids may ensure that proliferation of progenitor cells in the adult dentate gyrus is regulated across the range of adrenal corticoid activity, including both basal and stressful contexts. Although a small proportion of newly formed cells may express GR and MR, corticosterone probably regulates proliferation indirectly through other local cells.
新神经元在海马体齿状回中持续产生。众多因素调节神经元的产生速率。其中最重要的因素之一是肾上腺来源的皮质激素。皮质激素水平升高会抑制祖细胞的增殖，而通过肾上腺切除术去除皮质激素则会逆转这种情况。皮质激素介导这种调节的确切机制尚不清楚，但据信皮质激素是通过盐皮质激素受体（MR）和糖皮质激素受体（GR）发挥作用的。先前关于这些受体在调节细胞增殖中作用的报道得出了相互矛盾的结论。在此，我们使用成年雄性大鼠中这些受体的激动剂和拮抗剂来研究并阐明它们的作用。在植入皮质酮微丸以恢复基础水平的去肾上腺雄性大鼠中，用螺内酯阻断MR可增强增殖，而用GR拮抗剂米非司酮处理则没有效果。然而，米非司酮可逆转完整大鼠中额外皮质酮的抑制作用。醛固酮和RU362分别作为MR和GR的激动剂，均可降低去肾上腺大鼠的增殖，并且两种激动剂联合处理具有额外的抑制作用。这些结果清楚地表明，两种受体的占据对祖细胞增殖的作用方向相同。存在对皮质激素具有不同亲和力的两种受体，这可能确保成年齿状回中祖细胞的增殖在包括基础和应激状态在内的肾上腺皮质激素活性范围内受到调节。尽管一小部分新形成的细胞可能表达GR和MR，但皮质酮可能通过其他局部细胞间接调节增殖。
