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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘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显示睡眠纺锤体减少和记忆巩固缺陷。相比之下，人患有创伤后应激障碍的患病会导致睡眠中断，而噩梦与加剧有关恐惧记忆。越来越多的研究支持以下理论，即不经常使用的树突状刺是在睡眠期间修剪，从而通过增强经常增强的信号与噪声比来改善记忆突触连接。我们发表的初步数据表明，神经元中的树突状刺是编码最近的上下文恐惧记忆痕迹在睡眠期间在宽阔的情况下进行了扫描降尺度。此外，我们的数据指向睡眠期间杏仁核中树突状刺的广泛升级与海马中的广泛降尺度相比，表明情感的两个关键领域的突触内存电路受到差异调节。关于分子途径存在关键的知识差距参与睡眠期间的树突状脊柱升级和降尺度。拟议的研究将使用最先进的单核RNA测序，空间转录组学和靶向质量的组合光谱法以及新型的转基因小鼠模型和互补的人脑术后研究，建立了涉及上扫描和的分子信号通路的急需的基础睡眠期间恐惧记忆回路中突触的降低并确定涉及的新分子过程。因此，该提案的目的将大大利用专业知识和技术能力独特地通过健康和疾病的分子中心提供。预期数据将服务作为未来研究的基础，研究了精神疾病中这些途径的破坏和研究旨在确定治疗策略的新目标。