Molecular Mechanisms of Memory Consolidation in the Amygdala-Hippocampal Circuit

杏仁核-海马回路记忆巩固的分子机制

• 批准号: 10553869
• 负责人: Barbara Gisabella
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553869
• 关键词: Address; Affect; Amygdaloid structure; Area; Autopsy; Brain; Candidate Disease Gene; Cell Nucleus; Cell Separation; Cells; Centers of Research Excellence; Cessation of life; Data; Databases; Dendritic Spines; Disease; Diurnal Rhythm; Emotional; Euthanasia; Foundations; Fright; Future; Gene Expression; Genes; Health; Hippocampus; Hour; Human; Immunofluorescence Immunologic; Knowledge; Label; Learning; Maps; Mass Spectrum Analysis; Mediating; Memory; Memory impairment; Mental disorders; Molecular; Molecular Profiling; Mus; Neurons; Nightmare; Noise; Pathway interactions; Patients; Persons; Population; Post-Traumatic Stress Disorders; Process; Proteomics; Publishing; Quality of life; Regulation; Research Design; Rodent; Role; Sampling; Schizophrenia; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Sleep disturbances; Spermidine; Stimulus; Symptoms; Synapses; Technology; Testing; Time; Transgenic Mice; Vertebral column; Viral; Viral Vector; Wakefulness; cell type; circadian; conditioned fear; fear memory; improved; memory consolidation; mouse model; neuropsychiatric disorder; new therapeutic target; next generation; novel; single nucleus RNA-sequencing; sleep spindle; theories; transcriptome sequencing; transcriptomics; vector

Project Summary Sleep and memory dysfunction are key features across many psychiatric disorders. Patients with schizophrenia commonly display both decreased sleep spindles and memory consolidation deficits. In comparison, people suffering from post-traumatic stress disorder have sleep disruption and nightmares associated with heightened fear memories. A growing number of studies support the theory that infrequently used dendritic spines are pruned during sleep, thus improving memories by enhancing the signal to noise ratio of frequently reinforced synaptic connections. Our published and preliminary data demonstrates that dendritic spines in neurons that encoded a recent contextual fear memory trace are upscaled during sleep in the presence of broad downscaling. Furthermore, our data pointing to broad upscaling of dendritic spines in the amygdala during sleep compared to broad downscaling in the hippocampus indicates that synapses in two key areas of the emotional memory circuit are differentially regulated. There is a critical knowledge gap regarding the molecular pathways involved in dendritic spine upscaling and downscaling during sleep. The proposed studies will use a combination of state-of-the-art single nucleus RNA sequencing, spatial transcriptomics and targeted mass spectrometry along with a novel transgenic mouse model, and complementary human brain postmortem studies, to create a much-needed foundation of molecular signaling pathways involved in upscaling and downscaling of synapses in the fear memory circuit during sleep and identify new molecules involved in this process. Thus, the aims of this proposal will significantly leverage the expertise and technological capabilities uniquely offered through the Molecular Center of Health and Disease- COBRE. The expected data will serve as a foundation for future studies examining disruption of these pathways in psychiatric disorders, and studies designed to identify novel targets for therapeutic strategies.

项目概要 睡眠和记忆功能障碍是许多精神疾病的关键特征。精神分裂症患者 通常表现出睡眠纺锤波下降和记忆巩固缺陷。相比之下，人们 患有创伤后应激障碍的人会出现睡眠中断和噩梦 恐惧的回忆。越来越多的研究支持这样的理论：不常用的树突棘是 在睡眠期间修剪，从而通过增强经常强化的信号的信噪比来改善记忆 突触连接。我们发表的初步数据表明，神经元中的树突棘 编码最近的情境恐惧记忆痕迹在睡眠期间在广泛存在的情况下被放大 缩小规模。此外，我们的数据表明睡眠期间杏仁核中的树突棘广泛升级 与海马体的广泛缩小相比，表明情感的两个关键区域的突触 存储器电路采用差动调节。关于分子途径存在关键的知识差距 参与睡眠期间树突棘的放大和缩小。拟议的研究将使用 最先进的单核 RNA 测序、空间转录组学和目标质量的结合 光谱测定法以及新型转基因小鼠模型和补充人脑尸检 研究，为参与升级和​​优化的分子信号通路奠定了急需的基础 睡眠期间恐惧记忆回路中突触的缩小并识别参与此过程的新分子 过程。因此，该提案的目标将显着利用专业知识和技术能力 由健康与疾病分子中心 COBRE 独家提供。预期数据将服务 作为未来研究检查精神疾病中这些途径的破坏的基础，以及研究 旨在确定治疗策略的新靶点。