Fkbp5 modulation of prefrontal function.

项目摘要/摘要： 被广泛接受的模型认为，下缘皮质(IL)是恐惧的关键结构 在恐惧条件作用中不起作用的灭绝。令人惊讶的是，我们发现有选择地 IL中FK506结合蛋白5(FKBP5)表达减少减少习得和回忆 条件性恐惧。尽管临床数据表明FKBP5在创伤后应激障碍中起作用，但它确实是 尚不清楚FKBP5表达的差异单独是否会使个体易感或保护个体 来自创伤后应激障碍的发展。我们的数据表明，FKBP5在卵巢癌中的高表达 腹侧前额叶皮质(相当于人类的IL)可使人们易患上 创伤后创伤后应激障碍的发展由于直接刺激杏仁核中的IL输入会 没有减少恐惧习得，很可能是在击倒IL FKBP5后减少了恐惧习得 通过IL向其他皮质下结构的投射进行调节。条件性的习得 恐惧需要刺激基底外侧区的糖皮质激素和β-肾上腺素能受体 杏仁核。因此，IL可能通过调节糖皮质激素或激素来调节恐惧学习。 儿茶酚胺通过下丘脑外侧核(LHA)的输入释放 终末核(BNST)或孤束核(NTS)。在这个项目中，我们将测试这部小说 假说通过Fkpb5信号调节恐惧学习和记忆 IL投射至BNST、LHA或NTS的兴奋性。为了检验这一假设，我们首先 评价IL投射神经元中FKBP5选择性表达的减少或过表达 调节条件性恐惧的获得或回忆。接下来，我们将评估FKBP5是否 调节投射到BNST、LHA或LHA的IL神经元的内在或突触兴奋性 NTS采用膜片钳记录脑片逆行标记的IL投射。终于 我们将使用光遗传学来评估BNST、LHA或NTS的IL输入是否调制恐惧 学习和记忆。

Project Summary/Abstract: The widely accepted model proposes that the infralimbic cortex (IL) is a key structure for fear extinction that plays no role in fear conditioning. Surprisingly, we found that selectively decreasing expression of FK506 binding protein 5 (FKBP5) in IL reduced acquisition and recall of conditioned fear. Although clinical data suggest that FKBP5 plays a role in PTSD, it is unclear whether differences in FKBP5 expression alone could predispose or protect individuals from the development of PTSD. Our data suggests that higher expression of FKBP5 in the ventral medial prefrontal cortex (equivalent of IL in humans) could predispose people to the development of PTSD following trauma. Since direct stimulation of IL inputs in the amygdala do not reduce fear acquisition, the reduced fear acquisition after knocking down IL FKBP5 is likely to be mediated by IL projections to other subcortical structures. The acquisition of conditioned fear requires glucocorticoid and beta adrenergic receptor stimulation in the basolateral amygdala. Therefore, IL could modulate fear learning by modulating glucocorticoid or catecholamine release via inputs to the lateral hypothalamus (LHA), bed nucleus of the stria terminalis (BNST), or nucleus tractus solitarius (NTS). In this project, we will test the novel hypothesis that signaling via Fkpb5 modulates fear learning and memory by modulating the excitability of IL projections to the BNST, LHA, or NTS. To test this hypothesis, we will first evaluate whether reducing or overexpressing FKBP5 selectively in IL projection neurons modulates acquisition or recall of conditioned fear. Next, we will evaluate whether FKBP5 modulates the intrinsic or synaptic excitability of IL neurons projecting to the BNST, LHA, or NTS using patch-clamp recordings of retrogradely labeled IL projections in brain slices. Finally we will use optogenetics to evaluate whether IL inputs to the BNST, LHA, or NTS modulate fear learning and memory.