The Role of Fkbp5 in Anxiety Like Behaviors

 描述(申请人提供)：下丘脑-垂体-肾上腺轴功能障碍可导致糖皮质激素分泌不足或过多，这可能会影响大脑结构，如杏仁核和边缘下皮质，从而扰乱情绪学习。糖皮质激素信号受损会影响恐惧消退学习。在拟议的项目中，我将研究糖皮质激素受体与其调节因子之一FK结合蛋白5(FKBP5)的相互作用。由于FKBP5基因多态性与患创伤后应激障碍的风险增加有关，FKBP5表达的变化可能会影响恐惧消退学习和回忆。在目标1中，我将检测恐惧条件反射和恐惧消退过程中边缘皮质和血液中FKBP5基因和蛋白的变化。在目标2中，我将测试通过将表达FKBP5-shRNA的质粒注入下缘皮质来减少FKBP5的表达是否影响预先恐惧消退对恐惧消退回忆的影响。此外，在目标3中，我将测试FKBP5在下缘皮质表达的变化是否有助于慢性糖皮质激素激活后发现的受损消退。拟议的实验将阐明FKBP5和创伤后应激障碍之间的联系。

 DESCRIPTION (provided by applicant): Dysfunction of the hypothalamic-pituitary-adrenal axis can lead to insufficient or excessive glucocorticoid secretion which can disrupt emotional learning by affecting brain structures such as the amygdala and the infralimbic cortex. Impaired glucocorticoid signaling affects fear extinction learning. In the proposed project, I will examine the glucocorticoid receptor interaction with one of its regulators, the FK binding protein 5 (Fkbp5). Since Fkbp5 polymorphisms are associated with increased risk of developing post-traumatic stress disorder, changes in Fkbp5 expression may affect fear extinction learning and recall. In Aim 1, I will examine the mRNA and protein changes in Fkbp5 in the infralimbic cortex, and blood during fear conditioning and fear extinction. In Aim 2, I will test whether reducing the expression of Fkbp5 by infusing a plasmid expressing an Fkbp5-shRNA into the infralimbic cortex prior fear extinction affects fear extinction recall. Also, in Aim 3, I will test whether changes in Fkbp5 expression in the infralimbic cortex contributes to the impaired extinction found after chronic glucocorticoid activation. The proposed experiments will shed light on the association between Fkbp5 and PTSD.