生物谷报道：未成熟大脑具有熟练架构自身（神经系统）以适应生活环境改变的特性，这是神经生物学中最令人匪夷所思的一点。这种特性就是所谓的可塑性。然而，未成熟大脑的这一奇特可塑性仅见于被称为临界期的一段短暂的时间内。例如，儿童在属于早期临界期的婴幼儿阶段被剥夺正常视觉刺激，就会患上弱视，导致永久性的视力缺损。目前,研究人员通过比较经历视觉体验的幼鼠和成年鼠大脑的遗传区域，已经发现对大脑可塑性可能起关键作用的遗传活动的差异。托马索·彼左鲁索和同事在2007年3月1日出版的《神经元》杂志（肖尔出版社）上发表了该研究成果。
在试验过程中, 研究人员让幼鼠和成年鼠在黑暗中生活了3天，之后每隔一段时间让其适应正常光线，并对每只鼠的大脑视皮质的遗传区域反应进行分析。研究人员发现幼鼠大脑有特异性遗传活动，而成年鼠大脑则没有。此外，研究人员还意外发现这一视觉体验能够刺激幼鼠大脑里的组蛋白发生化学修饰，而成年鼠则无此发现。
组蛋白经由DNA缠绕，从而形成串珠样结构的核小体。组蛋白的化学修饰使DNA能够接触激活基因的区域。研究人员同时发现，受视觉刺激激活的基因能够调控其他基因的转录。转录是将DNA基因复制成RNA的过程，是制造蛋白的一张蓝图。为了确定组蛋白的化学修饰是否对大脑可塑性产生功能上的影响，研究人员做了一个试验，即给予成年鼠服用一种能够增加组蛋白化学修饰的药物。结果显示，成年鼠的视觉可塑性确实有所增加。
彼左鲁索和同事下结论道：我们的结果显示，视觉体验可在不同程度上激活幼鼠和成年鼠大脑视皮质中调控基因表达的胞内信号传导通路，并且这种发育下调节可以下调节成年鼠大脑视皮质中的可塑性发育。神经系统的重新架构有赖于组蛋白的化学修饰，而视觉体验刺激产生化学修饰的能力下降与临界期的终止具有相关性。同时他们还说道：我们所发现的这一机制可能对临界期的视皮质可塑性具有重要意义，并且临界期的终止可能与视皮质中的下调节有关。因此，产生于临界期终止阶段的可塑性发育下调节可能是由作用于细胞膜内、外的不同水平的多分子机制所引起。
Figure 1. Visual Stimulation Induces MSK Thr 581 Phosphorylation
(A) The number of pMSK-positive cells is increased by 15 min of visual stimulation. The activation is transient and returns to baseline at 40 min (dr, n = 7; 15 min, n = 11; 40 min, n = 4; one-way ANOVA, p = 0.003; post hoc Holm-Sidak: 15 min versus dr, p < 0.05; 15 min versus 40 min, p < 0.05; 40 min versus dr, p = 0.53). Hollow symbols represent data from single animals; filled symbols report average ± SEM. Data are normalized to the average of dr animals.
(B) Examples of pMSK staining in visual cortex of dr and 15 min mice. Cortical layers are indicated on the right. The inset shows the nuclear staining of pMSK as shown by a double staining for Neurotrace. Scale bar = 70 μm (10 μm for the inset).
(C) MSK phosphorylation induced by visual stimulation is blocked by inhibition of ERK. Average (±SEM) number of pMSK-positive cells (normalized to the dr value, dotted line) in visual cortex of mice visually stimulated for 15 min and treated with UO126. Significantly fewer positive cells are present in the treated cortex with respect to the contralateral untreated cortex (n = 6, paired t test, p = 0.01). The number of pMSK-positive cells in the cortex treated with the inhibitor vehicle is not different from that in the untreated contralateral cortex (n = 6, paired t test, p = 0.48). On the right, pMSK staining from a mouse visually stimulated for 15 min with one cortex infused with UO126. Scale bar = 60 μm.
(D) pMSK (red) and pERK (green) staining coexist in the same cells. Cells (n = 602) were classified as single-stained for pERK, single-stained for pMSK, or pMSK/pERK double-stained after inspection of z-stacks of confocal images. Scale bar = 14 μm.
原文出处:
Neuron March 1, 2007: 53 (5)
Developmental Downregulation of Histone Posttranslational Modifications Regulates Visual Cortical Plasticity
Elena Putignano, Giuseppina Lonetti, Laura Cancedda, Gianmichele Ratto, Mario Costa, Lamberto Maffei, and Tommaso Pizzorusso
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