Understanding Foxp2-Mediated Molecular Signaling in Fear Learning

了解恐惧学习中 Foxp2 介导的分子信号传导

基本信息

批准号：
10662864
负责人：
Olga Y Ponomareva
金额：
$ 19.45万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662864
关键词：
Address Adult Affect Amygdaloid structure Animal Disease Models Animals Attention deficit hyperactivity disorder Award Behavior Behavioral Cell Nucleus Cells Child Abuse and Neglect Cohort Studies Corpus striatum structure Data Development Disease Disease model Down-Regulation Emotional Emotions Estrous Cycle Extinction FOXP2 gene Feedback Female Fright Funding Gene Expression Profiling Genes Genetic Genetic Transcription Genomics Goals Intercalated Cell Ion Channel Knock-out Language Development Learning Learning Disorders Literature Lithium Mediating Mediator Memory Mental disorders Messenger RNA Molecular Molecular Biology Molecular Genetics Molecular Target Mus Neurons Pathway interactions Peptides Physicians Population Post-Traumatic Stress Disorders Regulation Reporting Research Proposals Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Role Scientist Sex Differences Shock Short-Term Memory Signal Pathway Signal Transduction Testing Time Tissue-Specific Gene Expression Training Transcriptional Regulation WNT Signaling Pathway Work antagonist behavioral study beta catenin cell type conditioned fear depressive symptoms emotion regulation experience fear memory forkhead protein genome wide association study genome-wide inhibitor knock-down knockout gene male marijuana use disorder mature animal member memory consolidation memory process nervous system development neural circuit neuromechanism neuropsychiatric disorder overexpression personalized medicine response single nucleus RNA-sequencing skills symptomatology transcription factor

项目摘要

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.

项目概要/摘要创伤后应激障碍 (PTSD) 是一种常见且令人衰弱的精神疾病，可用的治疗方法有限个性化治疗。最近的全基因组关联研究（GWAS）已经开始阐明与该疾病有关的重要靶基因。最近发现的目标之一是转录 Foxp2 因子。 Foxp2 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未知。在成年小鼠中，Foxp2 mRNA 在周围的闰细胞簇中表达基底外侧杏仁核。闰细胞对于条件性恐惧反应和恐惧具有重要的功能灭绝；然而，Foxp2 转录因子、其上游介体和下游靶标的作用，调节杏仁核中与恐惧相关的行为的作用仍然未知。最近的证据表明 Foxp2 受 Wnt 信号通路的多个成分调节，进而在反馈循环中发挥作用调节 Wnt 通路成员的调节。在这个提案中，我将测试 Foxp2 调节的假设恐惧学习的特定组成部分通过其与闰层中的 Wnt 信号通路相互作用杏仁核细胞。在目标 1 中，我将测试恐惧期间杏仁核中 Foxp2 的转录调节学习。我将使用 RT-PCR 对恐惧学习后的 Foxp2 转录进行时程分析 RNA 范围。我还将在 Foxp2 敲除后使用单核测序来表征 Foxp2 靶标恐惧学习后杏仁核内的特定细胞类型。最后，我会进行与恐惧相关的行为使用雄性和雌性成年小鼠进行杏仁核特异性 Foxp2 敲除的表征。在《Aim2》中，我会从机制上检验 Foxp2 在恐惧学习过程中受 Wnt 信号通路调节的假设， Ressler 实验室之前的研究成果建立在 Wnt 信号通路成分在成人中的作用的基础上学习和记忆。概述的 K08 提案将建立在我之前在发展路径方面的经验的基础上，分子生物学和遗传学，同时继续在疾病相关神经的哺乳动物模型中进行培训电路。该提案的最终目标是在收集信息的同时进一步提高我的技术和专业技能数据将构成在成为独立机构的道路上获得独立资金的基础医生科学家。