Transcriptomic Mechanisms of Formation and Persistence of Synapse Specific Long-Term Memory

突触特异性长期记忆形成和持续的转录组机制

• 批准号: 9896348
• 负责人: Sathyanarayanan V Puthanveettil
• 金额: $ 56.44万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896348
• 关键词: Afferent Neurons; Animal Model; Animals; Aplysia; Axon; Biological; Biology; Cell Culture System; Cell Nucleus; Cells; Data; Exposure to; Functional disorder; Gene Expression; Genes; Genetic Transcription; Gills; Hour; In Vitro; Invertebrates; Kinesin; Knowledge; Learning; Marines; Mediating; Memory; Memory Disorders; Messenger RNA; Microdissection; Molecular; Molecular Biology; Molecular Motors; Motor Neurons; Neurons; Neurotransmitters; Pathway Analysis; Perfusion; Phase; Protein Biosynthesis; Proteins; RNA; RNA Transport; Reflex action; Regulation; Role; Serotonin; Signal Pathway; Snails; Specificity; Structure; Synapses; Synaptic Transmission; System; Testing; Transcriptional Activation; Vertebrates; Withdrawal; analog; base; differential expression; experimental study; insight; interdisciplinary approach; long term memory; neural circuit; novel; postsynaptic neurons; programs; reconstitution; recruit; sea slug; synaptogenesis; therapeutic development; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Long-term memory (LTM) storage requires remodeling of pre-existing synapses and formation of new ones. While the necessity of transcription in the temporal phases of LTM such as formation and persistence has been described, we lack comprehensive information on how gene expression changes in a neural circuitry mediate the formation and persistence of LTM. In any of the animal models of learning, we do not know what components of the transcriptomes are recruited specifically in pre- or post-synaptic neurons for mediating the formation and persistence of LTM. Particularly we know very little about the gene expression changes required for the persistence of LTM. Lack of this knowledge is a critical barrier for deciphering the molecular underpinnings of synapse specificity and LTM. The central hypothesis of this proposal is that coordinated regulation of the pre- and the post-synaptic neuronal transcriptome mediate the formation and persistence of synapse specific LTM. We propose to test this hypothesis using the well-characterized neural circuitry of gill-withdrawal reflex (GWR) of the marine snail, Aplysia californica. Specifically, using a modified bifurcated sensory neuron-motor neuron culture, we will assess the changes in the subcellular transcriptome of pre-synaptic sensory neurons and post-synaptic motor neurons during the formation and persistence of the synapse specific LTM. Furthermore, the role of molecular motor kinesin mediated transport of RNAs from the cell body to synapses in synapse specific LTM will be determined. We anticipate that these experiments will facilitate the decoding of the gene expression program for the formation and persistence of LTM in components of a defined neural circuitry. Furthermore, our studies are expected to produce a ground- breaking impact on the basic biology of synapse specific LTM as well as to facilitate identification of novel candidates for the development of therapeutics for memory disorders.

项目总结 长时记忆(LTM)的存储需要对先前存在的突触进行重塑，并形成新的 一个。而转录在LTM的形成和持续等时间阶段的必要性 ，我们缺乏关于神经回路中基因表达如何变化的全面信息 调节LTM的形成和持续。在任何动物模型的学习中，我们都不知道 转录本的组成部分被特异性地招募到突触前或突触后神经元中，以介导 LTM的形成和持续。尤其是我们对基因表达的变化知之甚少 LTM的持久性所必需的。缺乏这种知识是破译分子的关键障碍。 突触特异性和LTM的基础。这一提议的中心假设是协调一致的 突触前和突触后神经元转录组的调节调节形成和 突触特异性LTM的持久性。我们建议使用刻画良好的 海螺缩鳃反射的神经回路。具体地说，使用 改良的感觉神经元-运动神经元培养，我们将评估亚细胞的变化 突触前感觉神经元和突触后运动神经元在形成和发育过程中的转录组 突触特异性LTM的持久性。此外，分子马达运动蛋白介导的运输的作用 在突触特异性LTM中，从细胞体到突触的RNA的数量将被确定。我们预计这些 实验将有助于解码基因表达程序的形成和持续 定义的神经电路的组件中的LTM。此外，我们的研究有望产生一个基础- 对突触特异性LTM的基础生物学的突破性影响以及促进新的 记忆障碍疗法研究的候选对象。