PDF(Pubmed)
Abstract：
Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.
摘要：
恐惧调理引起糖皮质激素的生理释放，有助于学习。作为糖皮质激素受体复合物中的伴侣，FKBP51调节应激诱导的糖皮质激素信号，并可能影响条件性恐惧反应。这项研究结合了分子和行为方法，以检查局部减少腹侧海马中FKBP51的表达是否足以影响与恐惧相关的行为。我们假设降低VH中的FKBP51表达将增加糖皮质激素信号传导以改变听觉恐惧条件。将成年雄性大鼠注射表达短发夹-RNA(shRNA)的腺相关病毒(AAV)载体,将FKBP5靶向到腹侧海马中以降低FKBP5水平或对照AAV。将FKBP5-shRNA注入腹侧海马可降低听觉恐惧的获得和回忆。尽管注射FKBP5-shRNA的动物在灭绝回忆过程中表现出较少的冻结，这种差异是由于恐惧回忆的减少，而不是灭绝的改善。减少腹侧海马FKBP51并不影响在空场测试或高架零迷宫测试中的探索行为，但在强迫游泳测试中确实增加了被动行为。这表明听觉恐惧回忆的减少并不是由于对急性压力的更积极的反应。此外，较低的腹侧海马FKBP51水平没有改变皮质酮的释放，以响应束缚应激，这表明恐惧回忆的减少不是由于皮质酮释放减少。我们的发现表明，腹侧海马中的FKBP51在调节恐惧学习过程和对急性应激的被动行为反应中起着选择性作用，而不是下丘脑-垂体-肾上腺轴反应性或探索性反应。
