Growth factor signaling in two-trial long-term memory formation in Aplysia

海兔两次试验长期记忆形成中的生长因子信号传导

• 批准号: 8649314
• 负责人: Ashley M Kopec
• 金额: $ 4.22万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2015-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649314
• 关键词: Actins; Address; Adult; Afferent Neurons; Animal Model; Aplysia; Axon; Behavior; Behavioral; Biological Models; Brain; Brain Injuries; CCAAT-Enhancer-Binding Proteins; Chimera organism; Cytoskeleton; DNA Sequence Rearrangement; Data; Dendritic Spines; Development; Disease; Environment; Family; Ganglia; Gene Expression; Genes; Growth; Growth Factor; Human; Kinesin; Learning; MAPK7 gene; Measures; Mediating; Memory; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Motor Neurons; Nature; Neuraxis; Neurodegenerative Disorders; Neuronal Plasticity; Neurosciences; Outcome; Pathology; Phase; Phosphorylation; Phosphotransferases; Play; Preparation; Proteins; Publishing; Reflex action; Regulation; Research Project Grants; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Synapses; System; Tail; Testing; Therapeutic Intervention; Time; Training; Transforming Growth Factor beta; Transforming Growth Factors; Withdrawal; Work; analog; base; bone; clinically relevant; developmental plasticity; human TGFBR2 protein; long term memory; nervous system disorder; neuronal cell body; neurotrophic factor; novel; public health relevance; receptor; spatiotemporal; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): Growth factors (GF) are secreted molecules important for many aspects of plasticity during development including axon outgrowth, actin cytoskeleton rearrangement, and synapse formation. There are multiple families of GFs, such as the neurotrophins and the transforming-growth factor ? (TGF?) superfamily, which mediate distinct outcomes during development by tightly regulated signaling in both space (e.g. at the cell body vs. at the synapse) and time (e.g. during synapse formation vs. during synapse stabilization). Importantly, GFs are highly evolutionarily conserved, making information derived from animal models informative for human neuroscience. A major challenge in neuroscience is to understand how the brain acquires and stores information for long periods of time, and how these long-term memories (LTMs) become susceptible to neurological disorders and neurodegenerative diseases. GFs are required for LTM, but it is not known how GF each family uniquely contributes to LTM formation. My work will directly explore the hypothesis that different GF families not only engage spatiotemporally coordinated signaling pathways that induce distinct gene expression profiles, but also synergistically interact to mediate LTM formation. This project aims to test several hypotheses by using the model organism Aplysia californica, which is a powerful system for elucidating the spatiotemporal coordination of molecular mechanisms relevant for adaptive behavioral change. I will focus on two GF families: neurotrophins signaling via the tropomysin-related kinase B receptor (TrkB) and TGF superfamily signaling via the TGF receptor II (TGF?r-II). First, I will test the hypothesis that different GF families engage spatiotemporally regulated signaling cascades which induce different gene expression profiles. To test this notion, I will block TrkB or TGF?r-II signaling using receptor body chimeras at either the soma or the synapse, during or after an analog form of LTM training, and then determine if mitogen-activated protein kinase (MAPK) activation, a protein required for LTM, is inhibited. Using the same methods, I will determine if the expression of evolutionarily conserved genes required for LTM formation, C/EBP, Uch, kinesin, and neurexin, are blocked by blocking GF signaling. Second, I will explore the behavioral relevance of observations derived at the molecular level by (i) blocking GF signaling at the soma and/or the synapse, during or after LTM training to determine if behavioral expression of LTM requires spatiotemporally regulated GF signaling, and (ii) testing whether or not GF signaling cascades synergistically interact to subserve LTM formation. This overall project will provide a better understanding of GF signaling during LTM formation. Elucidating the mechanism of GF signaling will both inform the field from a basic scientific perspective, as well as potentially provide clinically relevant hypotheses for therapeutic targets relevant to neurological disorders and related diseases.

描述（由申请人提供）：生长因子（GF）是分泌的分子，对于发育过程中可塑性的许多方面很重要，包括轴突的生长，肌动蛋白细胞骨架重排和突触形成。有多个GF家族，例如神经营养蛋白和转化增长因子？ （TGF？）超家族，哪些在两个空间中受到严格调节的信号传导（例如在细胞体与突触处的电源）和时间（例如，在突触形成期间与突触稳定期间的突触形成时），介导了不同的结果。重要的是，GF在高度进化上是保守的，从而使信息源自动物模型的人类神经科学信息。神经科学的一个主要挑战是了解大脑如何长期获取和存储信息，以及这些长期记忆（LTMS）如何容易受到神经系统疾病和神经退行性疾病的影响。 LTM需要GF，但尚不清楚GF每个家庭如何唯一贡献LTM的形成。我的工作将直接探讨以下假设：不同的GF家族不仅参与了诱导不同基因表达谱的时空协调信号通路，而且还协同相互作用以介导LTM形成。这 项目旨在通过使用模型有机体Aplysia Californica来检验几种假设，该系统是阐明与自适应行为变化相关的分子机制的时空协调的强大系统。我将重点关注两个GF家族：通过Tropomysin相关激酶B受体（TRKB）和TGF超家族信号传导神经营养蛋白信号传导通过TGF受体II（TGF？r-II）。首先，我将检验以下假设：不同的GF家族与诱导不同基因表达谱的时空调节信号级联反应。要测试这个概念，我将使用受体体嵌合体阻止TRKB或TGF？R-II信号传导 在LTM训练的模拟形式中或之后的SOMA或突触，然后抑制有丝分裂原激活的蛋白激酶（MAPK）激活LTM所需的蛋白质。使用相同的方法，我将确定LTM形成，C/EBP，UCH，驱动蛋白和神经蛋白所需的进化保守基因的表达是否通过阻止GF信号传导来阻止。 Second, I will explore the behavioral relevance of observations derived at the molecular level by (i) blocking GF signaling at the soma and/or the synapse, during or after LTM training to determine if behavioral expression of LTM requires spatiotemporally regulated GF signaling, and (ii) testing whether or not GF signaling cascades synergistically interact to subserve LTM formation.这个整体项目将更好地了解LTM组中GF信号。阐明GF信号的机制将从基本的科学角度为领域提供信息，并有可能为与神经系统疾病和相关疾病有关的治疗靶点提供临床相关的假设。