Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility.
Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility.
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DOI：
10.1038/mp.2014.96
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发表时间：
2015-06
影响因子：
11
通讯作者：
McEwen, B. S.
中科院分区：
文献类型：
--
作者：
Nasca, C.;Bigio, B.;Zelli, D.;Nicoletti, F.;McEwen, B. S.
为什么有些人屈服于压力，发展出使人衰弱的精神疾病，而另一些人在面对逆境时却能很好地适应？在理解大脑发育和功能对环境因素的反应中个体差异的神经基础方面存在差距。在这里，使用一种新的方法来筛选实验室动物的近交群体，我们确定了两个小鼠亚群：与弹性小鼠相比，表现出情绪相关异常的易感小鼠，更好地科普压力。这种方法结合分子和行为分析，使我们认识到，在海马，突触前mGlu2受体，抑制谷氨酸的释放，作为一个应激敏感的个体差异的标记，以应激诱导的情绪障碍。事实上，小鼠中的遗传mGlu2缺失导致对应激更严重的易感性，模拟易感小鼠亚群。此外，我们描述了一个潜在的机制，糖皮质激素，通过盐皮质激素受体（MR），通过下调mGlu2受体减少对压力的恢复力。我们还提供了一个机械的MR之间的联系和表观遗传控制的神经元突触的基础易感性的压力的经验。这里介绍的方法和表观遗传变稳态概念作为一个模型，用于识别基于生物标志物和潜在机制的个体差异，也提供了分子特征，可能是有用的翻译人类行为和精神病理学。
Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two sub-populations of mice: susceptible mice that show mood-related abnormalities compared to resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress sensitive marker of individual differences to stress-induced mood disorders. Indeed genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MR), decrease resilience to stress via down regulation of mGlu2 receptors. We also provide a mechanistic link between MR and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.
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影响因子：
7.4
作者：
Myers, Brent;McKlveen, Jessica M.;Herman, James P.
通讯作者：
Herman, James P.
DOI：
10.1073/pnas.1110444108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Liston, Conor;Gan, Wen-Biao
通讯作者：
Gan, Wen-Biao
DOI：
10.1073/pnas.1216100110
发表时间：
2013-03-19
影响因子：
11.1
作者：
Nasca, Carla;Xenos, Dionysios;Nicoletti, Ferdinando
通讯作者：
Nicoletti, Ferdinando
影响因子：
0.5
作者：
Kinnally, Erin L.;Mann, J. John
通讯作者：
Mann, J. John
DOI：
10.1073/pnas.0500398102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fraga, MF;Ballestar, E;Esteller, M
通讯作者：
Esteller, M