Dissection of genetic and circuit mechanisms underlying fear memory generalization.

剖析恐惧记忆泛化背后的遗传和回路机制。

• 批准号: 9417404
• 负责人: Priya Rajasethupathy
• 金额: $ 24.9万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9417404
• 关键词: Alleles; Animal Model; Animals; Anterior; Anxiety Disorders; Behavior; Brain; Brain region; CRISPR/Cas technology; Calcium; Chromosome Mapping; Chromosomes, Human, Pair 1; Communication; Data; Data Analyses; Detection; Dissection; Dorsal; Early Intervention; Equilibrium; Foundations; Freezing; Fright; Functional disorder; Future; Generations; Genes; Genetic; Goals; Hippocampus (Brain); Human; Image; Individual; Knock-in; Knock-in Mouse; Knock-out; Link; Memory; Memory impairment; Modeling; Mus; Names; Neurons; Neurosciences; Panic Disorder; Patients; Phobias; Population; Post-Traumatic Stress Disorders; Potassium Channel; Predisposing Factor; Prefrontal Cortex; Preventive Intervention; Quantitative Trait Loci; Recruitment Activity; Reproducibility; Research Personnel; Resolution; Resources; Retrieval; Risk; Role; Symptoms; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Variant; Viral; Wild Type Mouse; X Chromosome; base; conditioned fear; design; disability; experimental study; fear memory; fibroblast growth factor 13; insight; memory retrieval; mouse model; neuropsychiatric disorder; novel; optogenetics; public health relevance; relating to nervous system; response; trait; two-photon

 DESCRIPTION (provided by applicant): Anxiety disorders are a leading cause of disability, afflicting 5-10% of individuals worldwide with no existing cure. Fear generalization, in which conditioned fear responses occur in an altered, unconditioned context, is a primary symptom in many anxiety disorders such as phobia, panic disorder, and post-traumatic stress disorder (PTSD). Patients and animal models of PTSD consistently show altered activity in brain circuits such as the prefrontal cortex (PFC) and hippocampus, but precise circuit mechanisms and their causal role in fear generalization remain largely unclear. Furthermore, very little is known about the genetic factors that predispose individuals to PTSD. We have already shown that increased activity in the PFC to hippocampus circuits is sufficient to cause fear memory retrieval in an unconditioned context (fear memory generalization). Here, I propose to further dissect the role of circuit and genetic mechanisms of fear generalization behavior. The central hypothesis of this study is that dissection of the PFC to hippocampus circuit, as well as local hippocampal circuit dynamics, in genetic mouse models of fear generalization will provide significant insight into brain mechanisms of PTSD. Aim 1 and 2 will be focused on the generation of accurate and reproducible mouse models of fear generalization, which will then be used in Aim 3 to determine whether the local hippocampal network dynamics have ensemble features that are associated with increased fear generalization behavior. This project will yield novel insights regarding the important circuit level mechanisms of PTSD, while in the future, providing potential circuit-level handles for manipulation of neural activity toward therapeutic value.

 描述(由申请人提供)：焦虑症是导致残疾的主要原因，困扰着全球5%-10%的没有现有治疗方法的个人。恐惧泛化，即条件性恐惧反应发生在改变的、无条件的环境中，是许多焦虑症的主要症状，如恐惧症、恐慌障碍和创伤后应激障碍(PTSD)。创伤后应激障碍的患者和动物模型一直显示出大脑回路如前额叶皮质(PFC)和海马体的活动改变，但确切的回路机制及其在恐惧泛化中的因果作用在很大程度上仍不清楚。此外，人们对易患创伤后应激障碍的遗传因素知之甚少。我们已经证明，在非条件性环境中，PFC到海马体回路的活动增加足以引起恐惧记忆的提取(恐惧记忆泛化)。在这里，我建议进一步剖析恐惧泛化行为的回路和遗传机制的作用。这项研究的中心假设是，在恐惧泛化的遗传小鼠模型中，解剖PFC到海马区的回路以及局部海马区回路的动力学将为理解创伤后应激障碍的脑机制提供重要的见解。目标1和目标2将专注于产生准确和可重复的恐惧概括小鼠模型，然后在目标3中使用该模型来确定局部海马区网络动态是否具有与增加的恐惧概括行为相关的集合特征。该项目将对创伤后应激障碍的重要电路水平机制产生新的见解，同时在未来为操纵神经活动以实现治疗价值提供潜在的电路水平处理。