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mouse genetics; multimodality; neural circuit; optogenetics; recruit; remote control; response; skills; tool; unpublished works; virus genetics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.

项目摘要 /摘要 该提案的长期目标是建立致力于剖析的独立实验室 内侧前额叶皮层（MPFC）电路的基本行为在精神病学中变得不良适应 疾病。 MPFC在认知，记忆和情感行为中起关键作用 ADHD，痴呆以及焦虑和与创伤有关的疾病等疾病的适应不良。 MPFC项目 广泛到皮质关联区域，边缘中心以及中脑和脑干核，它们是独特的 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，我建议将学习的恐惧和恐惧灭绝作为阐明班级的入口点 行为基础的MPFC神经元的。恐惧联想的记忆促进生存，可以持续 一生，但是当刺激不再威胁时会熄灭。焦虑和创伤有关 疾病的终生患病率为28％，其特征是适应不良的威胁评估 导致不适当的恐惧反应。 MPFC子区域PL是表达学习恐惧所必需的 最近和遥远的时间点，但很大程度上是由于缺乏适当的工具，这是 PL中的远程痕量形式仍然是神秘的。此外，尚不清楚行为灭绝如何影响 PL中的记忆迹线，PL投影的类别神经元的恐惧行为行为仍然未知。 该提案的目的是确定1）PL中的远程内存跟踪如何形成2） PL投影神经元基于远程内存检索，3）灭绝如何影响PL遥控器件 痕迹。中心假设是可以根据其活动访问特定类别的MPFC神经元 在行为期间，随后根据其投影模式和行为函数进行表征。 该假设将使用尖端的神经科学技术与Trap2结合使用，这是一个新的 小鼠遗传工具，用于永久访问特定过程中瞬时激活的神经元 经验。拟议研究的完成将阐明行为函数和投影模式 PL神经元有助于远程内存检索，并确定其功能如何受到 灭绝。这些贡献很重要，因为它们将揭示功能电路组织 与精神疾病有关的基本依赖MPFC的恐惧行为。 一个世界知名的神经科学家团队将监督这项研究。博士。 Liqun Luo，Gregory Quirk，Vikaas Sohal，Marc Tessier-Lavigne和Mark Schnitzer，将提供新的培训，以联系 神经回路行为并提供职业建议。以及包括 其他课程和众多职业发展活动，该提案的完成将提供 Denardo博士在顶级研究机构确保独立教师职位的必要技能。