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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要长期记忆（LTM）存储需要重塑现有的突触并形成新的一个。而在LTM的时间阶段（例如形成和持久性）中转录的必要性已经描述了，我们缺乏有关基因表达如何变化神经回路的全面信息介导LTM的形成和持久性。在任何动物的学习模型中，我们都不知道转录组的成分是在突触前或突触后神经元中专门招募的，以介导 LTM的形成和持久性。特别是我们对基因表达的变化知之甚少 LTM的持久性所必需。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。该提议的中心假设是协调调节前和突触后神经元转录组介导形成和突触特异性LTM的持久性。我们建议使用良好的特征来检验这一假设加州Aplysia的海洋蜗牛的Gill-WithDrawal反射（GWR）的神经回路。具体来说，使用一个修饰的分叉感官神经元神经元培养，我们将评估亚细胞的变化在形成过程中，突触前感觉神经元和突触后运动神经元的转录组和突触特异性LTM的持久性。此外，分子运动动力蛋白介导的转运的作用将确定来自细胞体的RNA到突触特异性LTM中的突触。我们预计这些实验将促进基因表达程序的解码，以形成和持续 LTM在定义的神经回路的组件中。此外，我们的研究有望产生基础破坏对突触特异性LTM的基本生物学的影响以及促进新颖的鉴定为记忆障碍发展治疗学的候选人。