Understanding Foxp2-Mediated Molecular Signaling in Fear Learning

项目总结/摘要 创伤后应激障碍（PTSD）是一种常见的、使人衰弱的精神疾病， 个性化治疗。最近的全基因组关联研究（GWAS）已经开始阐明 与这种疾病有关的重要靶基因。最近发现的靶点之一是转录 Foxp 2因子。Foxp 2以前曾被认为与语言学习障碍有关，然而，它在成人中的作用， 恐惧学习是未知的。在成年小鼠中，Foxp 2 mRNA在周围的嵌入细胞簇中表达， 基底外侧杏仁核嵌入细胞在条件性恐惧反应和恐惧中起着重要的作用 然而，Foxp 2转录因子的作用，其上游介质和下游靶点， 调节杏仁核中与恐惧相关的行为仍然是未知的。最近的证据表明，Foxp 2 由Wnt信号通路的多个组分调节，反过来，在反馈回路中起作用， 调节Wnt途径成员的调节。在这个提议中，我将检验Foxp 2调节 恐惧学习的特定成分通过其与Wnt信号通路的相互作用，在嵌入的 杏仁核的细胞。在目标1中，我将测试恐惧过程中杏仁核中Foxp 2的转录调节 学习我将使用RT-PCR对恐惧学习后的Foxp 2转录进行时程分析， RNAscope。我还将在Foxp 2敲除后使用单核测序来表征Foxp 2靶点， 杏仁核内的特定细胞类型。最后，我将进行与恐惧相关的行为测试， 使用雄性和雌性成年小鼠用杏仁核特异性Foxp 2敲除进行表征。在AIM 2中，我将 机制上验证了恐惧学习过程中Foxp 2受Wnt信号通路调控的假设， 基于Ressler实验室先前的工作，该工作显示了Wnt信号通路组分在成年人中的作用。 学习和记忆。概述的K 08提案将建立在我以前在发展途径方面的经验基础上， 分子生物学和遗传学，同时继续在疾病相关的神经系统的哺乳动物模型的培训， 电路这个建议的最终目标是进一步提高我的技术和专业技能，同时收集 这些数据将成为获得独立资金的基础，从而成为独立的 物理科学家

Project Summary/Abstract Post-Traumatic Stress Disorder (PTSD) is a common and debilitating mental illness with limited available personalized treatments. Recent Genome-Wide Association Studies (GWAS) have begun to elucidate significant target genes implicated in this disease. One of these recently identified targets is the transcription factor Foxp2. Foxp2 has been previously implicated in language learning disorders, however, its role in adult fear learning is unknown. In adult mice, Foxp2 mRNA is expressed in clusters of Intercalated Cells surrounding the basolateral amygdala. Intercalated Cells are functionally important for conditioned fear response and fear extinction; however, the role of the Foxp2 transcription factor, its upstream mediators and downstream targets, in modulating fear-related behaviors in the amygdala remains unknown. Recent evidence suggests that Foxp2 is regulated by multiple components of the Wnt signaling pathway and, in turn, acts in a feedback loop to modulate regulation of Wnt pathway members. In this proposal, I will test the hypothesis that Foxp2 regulates specific components of fear learning through its interaction with the Wnt signaling pathway in the Intercalated Cells of the amygdala. In Aim 1, I will test transcriptional regulation of Foxp2 in the amygdala during fear learning. I will perform a time-course analysis of Foxp2 transcription after fear learning using RT-PCR and RNAscope. I will also use single nuclei sequencing following Foxp2 knockout to characterize Foxp2 targets in specific cell types within amygdala after fear learning. Finally, I will perform fear-related behavioral characterization with amygdala-specific Foxp2 knockout using male and female adult mice. In Aim2, I will mechanistically test the hypothesis that Foxp2 is regulated by Wnt signaling pathway during fear learning, building on prior work from the Ressler Lab that showed the role of Wnt signaling pathway components in adult learning and memory. The outlined K08 proposal will build on my prior experience in developmental pathways, molecular biology and genetics, while continuing training in a mammalian model of disease-relevant neural circuitry. The ultimate goal of this proposal is to further my technical and professional skills while collecting data that will form the basis for obtaining independent funding on a path to becoming an independent Physician-Scientist.