Cortico-Hippocampal Mechanisms of Context Memory

情境记忆的皮质-海马机制

• 批准号: 10595966
• 负责人: Jelena Radulovic
• 金额: $ 7.29万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595966
• 关键词: Affect; African American; Anxiety; Area; Behavioral; Biological; Biological Psychiatry; Brain; Cells; DNA; Data; Decision Making; Dementia; Dependence; Development; Disease; Ensure; Episodic memory; Extracellular Matrix; Foundations; Fright; Functional disorder; Future; Genetic; Goals; Hippocampus (Brain); Impairment; Inflammation; Inflammation Mediators; Inflammatory; Label; Link; LoxP-flanked allele; Mediating; Memory; Memory Loss; Memory impairment; Mental Depression; Mental disorders; Molecular; Monitor; Mus; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Physicians; Pilot Projects; Plant Roots; Population; Post-Traumatic Stress Disorders; Process; Publications; Publishing; Qualifying; Reporter; Research; Retrieval; Role; Scientist; Signal Transduction; Site; Stress; Synapses; System; Testing; Time; Toll-like receptors; Training; Viral; Woman; activity marker; base; career; cognitive function; conditional knockout; design; episodic like memory; experience; genetic manipulation; imaging approach; knock-down; member; memory consolidation; mouse model; neocortical; neurobiological mechanism; neuronal circuitry; neuropsychiatric disorder; parent project; postsynaptic; preservation; receptor; targeted treatment

SUMMARY The highest cognitive functions such as reasoning, planning, and decision-making, are all, directly or indirectly, influenced by our past personal experiences, which are represented in hippocampal-cortical circuits as episodic memories. Dysfunction of these circuits has been linked to the most prevalent and challenging mental disorders of our time, ranging from dementia to anxiety, depression, and post-traumatic stress disorder. Understanding the neurobiological mechanisms of episodic memory formation and retrieval are therefore essential for the development of effective molecular and circuit-based therapies for such disorders. We posit a key role of activity-dependent inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) DH-RSC circuit in the stabilization and persistence of stress-related memories. Aim 1 is designed to determine the contributions of discrete DH-RSC projections to early tagging of RSC and sustained inflammatory signaling in DH and RSC. Aim 2 will focus on the direct contribution of hippocampal Toll-like receptors (Tlr) to memory consolidation and induction of TGFb1 and Aim 3 will examine the contribution of TGFb to the cortical dependence of memories and deactivation of inflammatory signaling in the DH-RSC circuit. These aims will be tested in mouse models of episodic-like memories by applying projection-specific manipulations of the DH-RSC circuit, cell-specific genetic manipulations of Tlr9 and TGFb receptors, and quantitative molecular biologic and imaging approaches to monitor inflammatory signaling in memory circuits. We hope that circuit specific Tlr9/ TGFb signaling will emerge as candidate target for therapies for neuropsychiatric disorders rooted in episodic memory deficits. In this supplement, we propose to add Kendra Parker as a member in our project to study the role of Tlr9 in memory-related inflammatory signaling. Kendra Parker has defined her career goal explicitly as a future physician scientist. Our goal during her participation in this R01 project is to provide the training in research resulting in publications, and thus ensure that she receives a strong foundation toward that outcome. We welcome the opportunity to train an African American woman as a future leader in biological psychiatry, and in the field of neurobiology of memory in particular.

摘要 最高认知功能，如推理、计划和决策，都是， 直接或间接地受我们过去的个人经历的影响，这些经历体现在 作为情节记忆的海马区-皮质回路。这些回路的功能障碍 与我们这个时代最普遍和最具挑战性的精神障碍有关，从 痴呆症导致焦虑、抑郁和创伤后应激障碍。了解 因此，情景记忆形成和提取的神经生物学机制是必不可少的 用于开发有效的基于分子和电路的治疗此类疾病的方法。我们 活动依赖性炎症信号在离散的背海马区中的关键作用 (Dh)向脾后皮质(RSC)DH-RSC回路的投射 与压力相关的记忆的持久性。目标1旨在确定以下方面的贡献 离散的DH-RSC投射到RSC的早期标记和持续的炎症信号 卫生署和皇家莎士比亚公司。目标2将集中于海马Toll样受体(TLR)的直接作用 TGFb1和Aim 3对记忆巩固和诱导的作用 TGFb对大鼠记忆皮层依赖性及炎性信号失活的影响 DH-RSC电路。这些目标将在小鼠的情景式记忆模型中进行测试 应用DH-RSC电路的投影特异性操作，细胞特异性基因 TLR9和TGFb受体的操作及其定量分子生物学和成像 监测记忆回路中炎症信号的方法。我们希望特定的赛道 TLR9/TGFb信号通路将成为神经精神疾病治疗的候选靶点 病症根源于间歇性记忆缺陷。 在本增刊中，我们建议将肯德拉·帕克加入我们的项目，以研究 TLR9在记忆相关炎症信号中的作用。肯德拉·帕克给她下了定义 明确的职业目标是成为未来的内科科学家。我们在她参加这次R01期间的目标 该项目的目的是提供研究方面的培训，从而出版，从而确保她 为实现这一结果奠定了坚实的基础。我们欢迎有机会培训一名 非洲裔美国女性作为生物精神病学未来的领导者，以及在 特别是记忆的神经生物学。