The Role of Fkbp5 in Anxiety Like Behaviors

 描述（由申请人提供）：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量，这可通过影响大脑结构（如杏仁核和边缘下皮质）破坏情绪学习。糖皮质激素信号传导受损影响恐惧消退学习。在拟议的项目中，我将检查糖皮质激素受体与其调节因子之一，FK结合蛋白5（Fkbp 5）的相互作用。由于Fkbp 5多态性与发生创伤后应激障碍的风险增加有关，因此Fkbp 5表达的变化可能会影响恐惧消退学习和回忆。在目标1中，我将研究在恐惧条件化和恐惧消退过程中，Fkbp 5在边缘下皮层和血液中的mRNA和蛋白质变化。在目标2中，我将测试通过在恐惧消退之前将表达Fkbp 5-shRNA的质粒注入边缘下皮层来减少Fkbp 5的表达是否会影响恐惧消退回忆。此外，在目标3中，我将测试Fkbp 5表达的变化是否有助于慢性糖皮质激素激活后发现的消退受损。这些实验将揭示Fkbp 5与PTSD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.