Circuit mechanisms for prefrontal control of remote memory retrieval

项目总结/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 内侧前额叶皮层（mPFC）电路的行为，成为精神病患者适应不良 紊乱mPFC在认知、记忆和情绪行为中起着关键作用， 注意力缺陷多动障碍、痴呆症、焦虑症和创伤相关疾病的适应不良。微型PFC项目 广泛分布于皮层联合区、边缘系统中心、中脑和脑干核， 与mPFC依赖性行为有关mPFC如何协调其不同的预测， 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类的切入点 mPFC神经元的数量。对可怕联想的记忆促进了生存，并能持续一段时间。 但当刺激不再构成威胁时，它就会熄灭。焦虑和创伤相关 疾病的终生患病率为28%，其特征是适应不良的威胁评估， 导致不适当的恐惧反应mPFC亚区PL是表达习得性恐惧所必需的， 最近和遥远的时间点，但主要是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，目前还不清楚行为灭绝如何影响 PL中的记忆痕迹，以及恐惧行为背后的PL投射神经元的类别仍然未知。 这个建议的目的是确定1）远程记忆痕迹如何在PL中形成，2）哪些类的 PL投射神经元是远程记忆提取的基础，以及3）灭绝如何影响PL远程记忆 跟踪。中心假设是特定类别的mPFC神经元可以根据其活动进行访问 在行为过程中，并随后根据其投射模式和行为功能进行表征。 这一假设将使用尖端的神经科学技术与TRAP 2相结合进行测试，TRAP 2是一种新的神经科学方法。 小鼠遗传工具，用于永久访问在特定时间内短暂激活的神经元， 体验.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，并决定它们的功能如何受到 灭绝这些贡献是重要的，因为它们将揭示功能电路组织 潜在的mPFC依赖性恐惧行为与精神疾病有关。 一个世界知名的神经科学家团队将监督这项研究。Liqun Luo博士，Gregory Quirk博士，Vikaas Sohal，Marc Tessier-Lavigne和Mark Schnitzer，并将提供新的培训，将组织 神经回路的行为和提供职业建议。以及全面的培训计划，其中包括 额外的课程和众多的职业发展活动，完成这一建议将提供 DeNardo博士在顶级研究机构获得独立教师职位的必要技能。

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.