Cortico-hippocampal mechanisms of context memory

情境记忆的皮质海马机制

• 批准号: 10208618
• 负责人: Jelena Radulovic
• 金额: $ 79.7万
• 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/10208618
• 关键词: Affect; Anxiety; Area; Behavioral; Biochemical; Biological; Brain; Cells; Complement Factor B; DNA; Data; Decision Making; Dementia; Dependence; Development; Disease; Dorsal; Ensure; Episodic memory; Extracellular Matrix; Fright; Functional disorder; Gene Expression Profile; Genetic; Hippocampus (Brain); Hour; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Label; Link; LoxP-flanked allele; Mediating; Memory; Memory Loss; Memory impairment; Mental Depression; Mental disorders; Modeling; Modification; Molecular; Monitor; Mood Disorders; Mus; Nature; Neocortex; Neurons; Pathway interactions; Pattern; Pilot Projects; Plant Roots; Population; Post-Traumatic Stress Disorders; Process; Publishing; Qualifying; Receptor Signaling; Reporter; Research; Retrieval; Rodent; Role; Signal Pathway; Signal Transduction; Site; Stress; Synapses; System; TLR9 gene; Testing; Time; Toll-like receptors; Training; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Variant; Viral; activity marker; base; cognitive function; conditional knockout; conditioned fear; design; episodic like memory; experience; genetic manipulation; in vivo; knock-down; memory consolidation; mouse model; neocortical; neurobiological mechanism; neuronal circuitry; neuropsychiatric disorder; novel; postsynaptic; preservation; stress related disorder; targeted treatment

ABSTRACT 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. The current project focuses on systems consolidation, a process which, through sustained interactions between hippocampal and cortical circuits, leads to a lasting cortical representation of episodic memories. Based on existing evidence, including our own published and pilot data, we posit a key role of activity-dependent inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) in systems consolidation, including tagging, activation, and deactivation of the DH-RSC circuit. 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 by monitoring circuit activity through virally expressed signaling reporters in vivo. We also plan to apply quantitative molecular biologic and biochemical approaches that will enable us to determine the concentration- dependent TGFb effects on gene expression patterns associated with activation and deactivation of the DH- RSC circuit. We believe that advancing our understanding of neuronal inflammation in the organization of memory circuits will advance our fundamental knowledge of systems consolidation. At the same time, we hope that circuit-specific Tlr9/TGFb signaling will emerge as candidate target for therapies for neuropsychiatric disorders rooted in episodic memory deficits.

抽象的 推理、计划和决策等最高认知功能都是直接或直接的 间接地，受到我们过去的个人经历的影响，这些经历体现在海马皮质回路中 作为情景记忆。这些电路的功能障碍与最普遍和最具挑战性的问题有关 我们这个时代的精神障碍，从痴呆到焦虑、抑郁和创伤后应激障碍。 因此，了解情景记忆形成和检索的神经生物学机制 对于开发针对此类疾病的有效分子和基于回路的疗法至关重要。目前的 项目侧重于系统整合，这是一个通过系统之间持续互动的过程 海马和皮质回路，导致情景记忆的持久皮质表征。基于 现有证据，包括我们自己发布的和试点数据，我们认为依赖活动的关键作用 离散背海马 (DH) 投射到压后皮质 (RSC) 的炎症信号传导 系统整合，包括 DH-RSC 电路的标记、激活和停用。设计目标1 确定离散 DH-RSC 预测对 RSC 早期标记和持续的贡献 DH 和 RSC 中的炎症信号传导。目标2将重点关注海马Toll样的直接贡献 受体 (Tlr) 对记忆巩固和 TGFb1 诱导的作用，目标 3 将检查 TGFb 对记忆的皮质依赖性和 DH-RSC 中炎症信号的失活 电路。这些目标将通过应用特定的投影在情景记忆的小鼠模型中进行测试 DH-RSC 回路的操作、Tlr9 和 TGFb 受体的细胞特异性遗传操作，以及 通过体内病毒表达的信号报告基因监测电路活动。我们也打算申请 定量分子生物学和生化方法将使我们能够确定浓度- TGFb 对与 DH- 激活和失活相关的基因表达模式的影响 RSC 电路。我们相信，加深我们对组织中神经元炎症的理解 存储电路将增进我们对系统整合的基础知识。同时，我们希望 电路特异性 Tlr9/TGFb 信号传导将成为神经精神治疗的候选靶标 根源于情景记忆缺陷的疾病。