齿状回中的 Sirtuin 活性有助于慢性应激诱导的行为和海马细胞外信号调节蛋白激酶 1 和 2 级联变化。
Sirtuin activity in dentate gyrus contributes to chronic stress-induced behavior and extracellular signal-regulated protein kinases 1 and 2 cascade changes in the hippocampus.
机构信息
Neuroscience Program, Tulane University, New Orleans, Louisiana.
出版信息
Biol Psychiatry. 2013 Dec 15;74(12):927-35. doi: 10.1016/j.biopsych.2013.07.029. Epub 2013 Sep 5.
BACKGROUND
Exposure to chronic stress produces negative effects on mood and hippocampus-dependent memory formation. Alterations in signaling cascades and histone acetylation present a mechanism of modulation of transcription that may underlie stress-dependent processes in the hippocampus critical to learning and memory and development of depressive behaviors.
METHODS
The rat model of chronic variable stress (CVS) was used to investigate the role of changes in protein acetylation and other molecular components of hippocampus-dependent memory formation and anhedonic behavior in response to CVS.
RESULTS
Chronic variable stress treatment decreased both extracellular signal-regulated protein kinases 1 and 2 activation and Bcl-2 expression in all three regions of the hippocampus that corresponded behaviorally with a decrease in memory for the novel object location task and increased anhedonia. Extracellular signal-regulated protein kinases 1 and 2 activation was not significantly affected in the amygdala and increased in the medial prefrontal cortex by CVS. Chronic variable stress had no significant effect on activation of Akt in the hippocampus. We investigated molecular and behavioral effects of infusion of the sirtuin inhibitor, sirtinol, into the dentate gyrus (DG). Sirtinol infusion into the DG prevented the CVS-mediated decrease in extracellular signal-regulated protein kinases 1 and 2 activity and Bcl-2 expression, as well as histone acetylation in the DG previously observed following CVS. This corresponded to enhanced performance on the novel object location memory task, as well as reduced anhedonic behavior.
CONCLUSIONS
These results suggest that changes in sirtuin activity contribute to changes in molecular cascades and histone acetylation within the hippocampus observed following CVS and may represent a novel therapeutic target for stress-induced depression.
背景
慢性应激会对情绪和海马体依赖的记忆形成产生负面影响。信号转导通路和组蛋白乙酰化的改变提供了一种转录调节的机制，这种机制可能是海马体中与学习和记忆以及抑郁行为发展有关的应激依赖性过程的基础。
方法
采用慢性可变应激（CVS）大鼠模型，研究海马体中蛋白质乙酰化和其他分子成分的变化，以及在慢性可变应激反应中与学习和记忆以及快感缺失行为有关的快感缺失行为。
结果
慢性可变应激处理降低了海马体三个区域的细胞外信号调节激酶 1 和 2 的激活和 Bcl-2 的表达，这与新物体位置任务记忆的减少和快感缺失的增加相一致。细胞外信号调节激酶 1 和 2 的激活在杏仁核中没有显著影响，而在中前额叶皮层中则增加。慢性可变应激对海马体中 Akt 的激活没有显著影响。我们研究了将组蛋白去乙酰化酶抑制剂 sirtinol 输注到齿状回（DG）的分子和行为效应。DG 中的 sirtinol 输注阻止了 CVS 介导的细胞外信号调节激酶 1 和 2 活性和 Bcl-2 表达的降低，以及先前观察到的 CVS 后 DG 中的组蛋白乙酰化。这与新物体位置记忆任务的表现提高以及快感缺失行为的减少相对应。
结论
这些结果表明，组蛋白去乙酰化酶活性的变化导致了 CVS 后海马体中分子级联和组蛋白乙酰化的变化，并且可能代表了应激诱导性抑郁的一个新的治疗靶点。
Zotero 插件