Molecular Mechanisms of Memory Consolidation in the Amygdala-Hippocampal Circuit

项目摘要 睡眠和记忆障碍是许多精神障碍的关键特征。精神分裂症患者 通常表现为睡眠纺锤体减少和记忆巩固缺陷。相比之下，人们 患有创伤后应激障碍的人有睡眠障碍和与高度紧张相关的噩梦 恐惧记忆。越来越多的研究支持这一理论，即不常用的树突是 在睡眠期间进行修剪，从而通过提高经常增强的信号的信噪比来改善记忆 突触连接。我们公布的初步数据表明，神经元中的树突棘 编码了最近的背景恐惧记忆痕迹在睡眠期间在布罗德的存在下被放大 缩小规模。此外，我们的数据指出，睡眠期间杏仁核中树突棘的广泛向上伸展 相比于海马体的广泛缩小表明，突触在情绪的两个关键区域 对存储电路进行差动调节。关于分子途径，有一个关键的知识缺口。 在睡眠期间参与树突棘突的放大和缩小。拟议的研究将使用 结合最新的单核RNA测序、空间转录和靶向质量 光谱，以及一种新的转基因小鼠模型，以及人脑死后补充 研究，以创建一个急需的分子信号通路的基础，涉及到放大和 降低睡眠中恐惧记忆回路中突触的比例，并识别与此相关的新分子 进程。因此，这项提案的目标将极大地利用专门知识和技术能力 由分子健康和疾病中心-科布雷独家提供。预期的数据将有助于 作为未来研究精神障碍中这些通路中断的基础，以及研究 旨在确定治疗策略的新靶点。

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.