Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear
Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear
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DOI：
10.1101/lm.043000.116
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发表时间：
2017-04-01
影响因子：
2
通讯作者：
Porter, James T.
中科院分区：
文献类型：
--
作者：
Criado-Marrero, Marangelie;Silva, Roberto J. Morales;Porter, James T.
影响心理弹性对创伤后应激障碍（PTSD）发展的因素尚不清楚。临床研究将PTSD与FK506结合蛋白5 （FKBP5）多态性联系起来。然而，尚不清楚FKBP5表达的变化是否会对ptsd样症状产生弹性或易感性。在这项研究中，我们以大鼠为动物模型，研究FKBP5在边缘下（IL）或边缘前（PL）内侧前额叶皮层是否调节恐惧条件反射或消退。首先，我们检测了FKBP5在IL和PL中在恐惧条件反射或消退过程中的表达。与PL中FKBP5的稳定表达相反，FKBP5在IL中的表达在恐惧条件反射后增加，即使在消失后也保持升高，这表明IL中FKBP5的水平可能调节恐惧条件反射或消失。与这种可能性一致的是，通过在IL中局部注入FKBP5- shrna来降低FKBP5的基础表达可以减少恐惧条件反射。此外，降低IL - FKBP5，在恐惧记忆巩固后，消退记忆增强，表明IL - FKBP5反对消退记忆的形成。我们的研究结果表明，降低IL中FKBP5的表达足以减少恐惧习得和增强恐惧消退，并提示FKBP5在腹侧内侧前额叶皮层的低表达可能有助于PTSD的恢复。
The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5-shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD.