Genomic Approaches to Deciphering Memory Circuits

破译记忆回路的基因组方法

• 批准号: 8542899
• 负责人: JINGYUE JU
• 金额: $ 38.14万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542899
• 关键词: Address; Afferent Neurons; Animal Model; Animals; Antibodies; Aplysia; Attention; Behavior; Bioinformatics; Biology; Biomedical Engineering; Biomedical Research; Brain; Cell Culture System; Cell Culture Techniques; Cell Polarity; Cell physiology; Cells; Characteristics; Coculture Techniques; Communication; Complement; Distal; Distant; FMRFamide; Fright; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genomics; Gills; Goals; Growth Cones; Human; In Vitro; Individual; Interneurons; Investigation; Learning; Maintenance; Memory; Memory Loss; Mental Depression; Messenger RNA; Methodology; MicroRNAs; Microdissection; Modality; Modeling; Molecular; Motor Neurons; Nerve; Neurites; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurosciences; Pathway interactions; Pattern; Peripheral; Physiological; Polyadenylation; Presynaptic Terminals; Process; Property; Proteins; RNA; RNA Interference; Reflex action; Regulator Genes; Research; Resolution; Role; Sensory; Serotonin; Signal Transduction; Site; Small RNA; Synapses; System; Systems Analysis; Systems Biology; Technology; Testing; Time; Transcript; Translations; Ursidae Family; Withdrawal; base; cell type; cost; deep sequencing; expectation; experience; functional genomics; interest; laser tweezer; learned behavior; long term memory; member; nervous system disorder; neural circuit; neuronal cell body; neuronal growth; polarized cell; protein distribution; reconstitution; response; success; synaptic function; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): The objective of the proposed research is to conduct a thorough single-cell and cell-compartment gene expression study through the application of high throughput genomic technologies to identify the genomic bases of neuronal identity, polarity and plasticity. Utilizing the well-studied gill withdrawal reflex memory circuit from the model organism Aplysia californica, our goal is to define systematically the molecular repertoire (genomic blueprint) of the neurites and individual synapses of the key neurons that make up this cellular ensemble. We will define the compartmental transcriptomes (the sets of mRNAs, miRNAs and other ncRNAs) within the components of the functional circuit (cells and synapses), which are reconstituted in vitro by co- culture of 2-4 of its best characterized cells (L7 motor neuron, sensory neuron, stimulatory and inhibitory interneurons). This fully operational neural circuit reconstructed in cell culture bears many important properties of the intact circuit, and has been used with great success to ascertain the molecular underpinnings of memory formation in Aplysia, numerous aspects of which are conserved within the animal kingdom, including in the human brain. The systems biology approach will be applied to reveal gene regulatory networks and their potential role in the establishment and maintenance of long-term memory using learned fear as an experimental paradigm, focusing on synaptic mechanisms of long-term facilitation (LTF) and depression (LTD). We will use this genomic and systems biology approach to explore the following three fundamental brain mechanisms: (1) the molecular basis of neuronal identity, by revealing those transcripts that are unique to or shared among these neurons or specialized synapses; (2) the molecular signals controlling cellular polarity and the formation of the precise pattern of interconnections which underlie behavior, in part directed by the distribution of mRNAs in the central and peripheral compartments of these cells; and (3) the molecular basis of synapse-specific neuronal plasticity and neuronal growth, with special attention paid to the mRNA repertoire within the individual synapses at the junctions between pairs of pre- and post-synaptic neurons. The combined approach will take advantage of an already established team of experts in genomics, bioengineering, neuroscience, and bioinformatics. Though these paradigms will be established in the large well-characterized neurons of Aplysia, the mechanisms revealed and the technologies developed will have a broad impact in the biology of any polarized cell type with asymmetric distribution of RNAs and proteins.

描述（由申请人提供）：拟议的研究的目的是通过应用高通量基因组技术来进行彻底的单细胞和细胞室基因表达研究，以鉴定神经元认同，极性和可塑性的基因组基础。我们的目标是利用模型生物体aplysia aplysia aplysia aplysia aplysia撤回反射记忆电路，我们的目标是系统地定义神经突的分子曲目（基因组蓝图），以及关键神经元的单个突触，这些神经元的单个突触，这些神经元的构成了这个细胞组合。我们将在功能回路（细胞和突触）内定义区室转录组（miRNA，miRNA和其他NCRNA的集合），它们通过其最佳特征性细胞的2-4（L7）（L7）在体外重构。运动神经元，感觉神经元，刺激性和抑制性中间神经元）。这种在细胞培养中重建的完全运行的神经回路具有完整电路的许多重要特性，并已成功地用于确定Aplysia记忆形成的分子基础，其中许多方面在动物王国中保守，包括在包括中的动物王国。人脑。系统生物学方法将应用于揭示基因调节网络及其在建立和维持长期记忆中的潜在作用，使用学识渊博的恐惧作为实验范式，重点是长期促进（LTF）和抑郁症的突触机制（LTD）（LTD） ）。我们将使用这种基因组和系统生物学方法来探索以下三种基本脑机制：（1）神经元认同的分子基础，通过揭示那些在这些神经元或专业突触中独有或共享的转录本； （2）控制细胞极性的分子信号以及基础行为基础的精确模式的形成，部分由这些细胞中央和外围隔室中mRNA分布的部分指导； （3）突触特异性神经元可塑性和神经元生长的分子基础，特别关注了单个突触前和突触后神经元之间交界处的个体突触中的mRNA库。联合方法将利用已经建立的基因组学专家团队，生物工程，神经科学和生物信息学。尽管这些范式将在众多的呼吸酶特征性神经元中建立，但所揭示的机制和开发的技术将对任何极化细胞类型的生物学产生广泛的影响，并具有RNA和蛋白质的不对称分布。