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.

摘要 最高的认知功能，如推理、计划和决策，都是直接或间接的。 间接地，受到我们过去的个人经历的影响，这些经历在大脑皮层回路中表现出来。 作为情景记忆。这些回路的功能障碍与最普遍和最具挑战性的 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提取的神经生物学机制， 对于开发针对此类疾病的有效分子和基于电路的疗法至关重要。当前 项目的重点是系统整合，这一过程通过系统之间的持续互动， 海马和皮层回路，导致情节记忆的持久皮层表征。基于 现有的证据，包括我们自己发表的和试点数据，我们认为活动依赖的关键作用， 大鼠背海马（DH）向压后皮质（RSC）的离散投射中的炎症信号传导 系统整合，包括DH-RSC电路的标记、激活和停用。Aim 1设计 确定离散DH-RSC预测对RSC早期标记和持续的 DH和RSC中的炎症信号传导。目的2将重点关注海马Toll样蛋白的直接作用。 受体（Tlr）对记忆巩固和TGF β 1诱导的作用，Aim 3将研究Tlr对记忆巩固和TGF β 1诱导的作用。 TGF β对DH-RSC中记忆的皮层依赖性和炎症信号的失活 电路.这些目标将通过应用特定投射技术在小鼠的情景记忆模型中进行测试。 DH-RSC回路的操纵，Tlr 9和TGF β受体的细胞特异性遗传操纵，以及 通过体内病毒表达的信号报告子监测回路活性。我们还计划申请 定量分子生物学和生物化学方法，使我们能够确定浓度- 依赖性TGF β对与DH-1激活和失活相关的基因表达模式的影响 RSC电路。我们相信，推进我们对组织中神经元炎症的理解， 存储器电路将推进我们的系统整合的基础知识。同时，我们希望 回路特异性Tlr 9/TGFb信号传导将成为神经精神疾病治疗的候选靶点， 源于情景记忆缺失的疾病