Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
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DOI：
10.1371/journal.pone.0037060
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
van den Burg EH
中科院分区：
文献类型：
--
作者：
Jurek B;Slattery DA;Maloumby R;Hillerer K;Koszinowski S;Neumann ID;van den Burg EH
神经元中的 c-Raf – MEK1/2 – ERK1/2 丝裂原激活蛋白激酶 (MAPK) 细胞内信号级联在控制各种行为（包括社交行为和焦虑）中发挥着重要作用。这些作用与催产素 (OXT) 的作用部分重叠，并且已表明 OXT 激活下丘脑（雄性）和海马（雌性）大鼠中的 MAPK 通路。在这里，通过结合行为（亮/暗盒）和生化分析（蛋白质印迹），我们测试了两个假设：（i）OXT 在女性下丘脑内具有抗焦虑作用，（ii）这种作用以及哺乳相关的抗焦虑作用取决于 MAPK 通路的募集。我们发现，当双侧注射到下丘脑室旁核 (PVN) 时，OXT 会减少处女的焦虑样行为，并且这种效果取决于 MEK1/2 的磷酸化。哺乳期的 MAPK 通路激活通过高磷酸化 (p) MEK1/2 水平和 ERK1 的核转位来明显体现。高 pMEK1/2 水平对于哺乳期间通常观察到的抗焦虑表型是必要的。有趣的是，哺乳期大鼠中的外源性 OXT 降低了 pMEK1/2 水平，但对焦虑没有伴随作用，这表明 OXT 受体激活可以导致招募额外的细胞内途径来调节 MEK 活性。还有其他途径可能包括 MEK，但随后不会激活 ERK，因为我们没有观察到 OXT 诱导的 ERK 磷酸化有任何增加。这些结果共同表明，MAPK 通路，尤其是 MEK1/2，在雌性大鼠焦虑样行为的调节中发挥着重要作用。
The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) intracellular signalling cascade in neurons plays important roles in the control of a variety of behaviours, including social behaviours and anxiety. These roles partially overlap with those described for oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway in the hypothalamus (of male), and hippocampus (of female) rats. Here, by combining behavioural (light/dark box) and biochemical analyses (western blotting), we tested two hypotheses: (i) that OXT is anxiolytic within the hypothalamus of females, and (ii) that this effect, as well as that of lactation-associated anxiolysis, depends on the recruitment of the MAPK pathway. We found that, when injected bilaterally into the hypothalamic paraventricular nucleus (PVN), OXT decreased anxiety-like behaviour in virgins, and that this effect depended on phosphorylation of MEK1/2. MAPK pathway activation in lactation was evident by high phosphorylated (p) MEK1/2 levels, and nuclear translocation of ERK1. The high pMEK1/2 levels were necessary for the anxiolytic phenotype typically observed during lactation. Interestingly, exogenous OXT in lactating rats reduced pMEK1/2 levels without a concomitant effect on anxiety, indicating that OXT receptor activation can lead to recruitment of additional intracellular pathways to modulate MEK activity. Still other pathways could include MEK, but without subsequent activation of ERK, as we did not observe any increase in OXT-induced ERK phosphorylation. Together the results demonstrate that the MAPK pathway, especially MEK1/2, is critically involved in the regulation of anxiety-like behaviour in female rats.
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