Circuit mechanisms for prefrontal control of remote memory retrieval

远程记忆检索前额控制的电路机制

• 批准号: 9900869
• 负责人: Laura Anne DeNardo
• 金额: $ 17.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900869
• 关键词: Address; Affect; Animals; Anxiety; Anxiety Disorders; Area; Attention; Attention deficit hyperactivity disorder; Axon; Behavior; Behavioral; Brain; Brain Stem; Brain region; Cell Nucleus; Code; Cognition; Complex; Data; Dementia; Development; Disease; Extinction (Psychology); Faculty; Foundations; Fright; Future; Genetic; Goals; Hypothalamic structure; Institution; Laboratories; Learning; Link; Logic; Maps; Measures; Medial; Mediating; Memory; Mental disorders; Microscope; Midbrain structure; Muscimol; Neurons; Neurosciences; Outcome; Output; Pattern; Pharmacology; Play; Positioning Attribute; Prefrontal Cortex; Prevalence; Process; Reporter; Research; Role; Secure; Site; Stimulus; Technology; Testing; Thalamic structure; Therapeutic Intervention; Time; Training; Trauma; Work; base; career; career development; cell type; conditioned fear; emotional behavior; experience; fear memory; genetic approach; insight; memory consolidation; memory retrieval; mouse genetics; multimodality; neural circuit; optogenetics; recruit; remote control; response; skills; tool; unpublished works; virus genetics

PROJECT SUMMARY / ABSTRACT The long-term goal of this proposal is to establish successful independent laboratory focused on dissecting medial prefrontal cortex (mPFC) circuits underlying behaviors that become maladaptive in psychiatric disorders. mPFC plays a critical role in cognition, memory, and emotional behaviors which become maladaptive in diseases such as ADHD, dementia, and anxiety and trauma-related disorders. mPFC projects widely to cortical association areas, limbic centers, and midbrain and brainstem nuclei which are uniquely implicated in mPFC-dependent behaviors. How does mPFC coordinate its diverse projections to give rise to specific behaviors? Here I propose to use learned fear and fear extinction as entry points to elucidate classes of mPFC neurons that underlie behavior. Memories of fearful associations promote survival and can last a lifetime, but become extinguished when a stimulus no longer poser threat. Anxiety and trauma-related disorders have a lifetime prevalence of 28% and are characterized by maladaptive threat assessment that leads to inappropriate fear responses. The mPFC subregion PL is required for expression of learned fear at recent and remote time points, but, largely due to the lack of appropriate tools, the processes by which the remote trace forms in PL remains mysterious. Furthermore, it is unclear how behavioral extinction affects the memory trace in PL, and the classes of PL projections neurons underlying fearful behaviors remain unknown. The objective of this proposal is to determine 1) how the remote memory trace forms in PL, 2) which classes of PL projection neurons underlie remote memory retrieval, and 3) how extinction impacts the PL remote memory trace. The central hypothesis is that specific classes of mPFC neurons can be accessed based on their activity during behavior, and subsequently characterized based on their projection patterns and behavioral function. This hypothesis will be tested using cutting-edge neuroscience technologies in combination with TRAP2, a new mouse genetic tool for permanently accessing neurons that are transiently activated during a particular experience. Completion of the proposed studies will elucidate the behavioral function and projection patterns of PL neurons that contribute to remote memory retrieval, and determine how their function is influenced by extinction. These contributions are significant because they will reveal the functional circuit organization underlying mPFC-dependent fear behaviors that are relevant to psychiatric disorders. A team of world-renowned neuroscientists will oversee this research. Drs. Liqun Luo, Gregory Quirk, Vikaas Sohal, Marc Tessier-Lavigne, and Mark Schnitzer and will provide new training to link the organization of neural circuits to behavior and offer career advice. Together with a comprehensive training plan that includes additional coursework and numerous career development activities, completion of this proposal will provide the necessary skills for Dr. DeNardo to secure an independent faculty position at a top research institution.

项目概要/摘要 该提案的长期目标是建立成功的独立实验室，专注于解剖 内侧前额皮质（mPFC）电路导致精神科适应不良的潜在行为 失调。 mPFC 在认知、记忆和情绪行为中发挥着至关重要的作用， 多动症、痴呆、焦虑和创伤相关疾病等疾病的适应不良。 mPFC 项目 广泛应用于皮质联合区、边缘中心、中脑和脑干核团，这些都是独特的 与 mPFC 依赖性行为有关。 mPFC 如何协调其不同的预测以产生 具体行为？在这里我建议使用习得性恐惧和恐惧消退作为阐明阶级的切入点 行为背后的 mPFC 神经元。可怕联想的记忆可以促进生存，并且可以持续很长时间 一生，但当刺激不再构成威胁时就会消失。焦虑和创伤相关 疾病的终生患病率为 28%，其特征是适应不良威胁评估： 导致不适当的恐惧反应。 mPFC 子区域 PL 是表达习得性恐惧所必需的 最近和遥远的时间点，但是，很大程度上由于缺乏适当的工具， PL 中的远程跟踪形式仍然是神秘的。此外，尚不清楚行为灭绝如何影响 PL 中的记忆痕迹以及潜在恐惧行为的 PL 投射神经元的类别仍然未知。 该提案的目标是确定 1) 远程内存跟踪如何在 PL 中形成，2) 哪些类 PL 投射神经元是远程记忆检索的基础，3）消退如何影响 PL 远程记忆 痕迹。中心假设是可以根据 mPFC 神经元的活动来访问特定类别的神经元 行为过程中，随后根据他们的投射模式和行为功能进行表征。 这一假设将使用尖端神经科学技术与 TRAP2 相结合进行测试，TRAP2 是一种新的 小鼠遗传工具，用于永久访问在特定期间短暂激活的神经元 经验。完成拟议的研究将阐明行为功能和投射模式 PL 神经元有助于远程记忆检索，并确定其功能如何受到以下因素的影响 灭绝。这些贡献意义重大，因为它们将揭示功能电路的组织 与精神疾病相关的潜在 mPFC 依赖性恐惧行为。 一个由世界知名的神经科学家组成的团队将监督这项研究。博士。罗立群、格雷戈里·奎克、维卡斯 Sohal、Marc Tessier-Lavigne 和 Mark Schnitzer 将提供新的培训，以将组织联系起来 行为的神经回路并提供职业建议。连同全面的培训计划，其中包括 额外的课程作业和众多的职业发展活动，完成本提案将提供 德纳多博士拥有在顶级研究机构获得独立教职职位所需的技能。