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

描述(申请人提供)：生长因子(GF)是一种分泌分子，在发育过程中对许多方面的可塑性都很重要，包括轴突生长、肌动蛋白细胞骨架重排和突触形成。GFS有多种家族，如神经营养因子和转化生长因子？(转化生长因子？)超家族，在发育过程中通过在空间(例如细胞体和突触)和时间(例如在突触形成和突触稳定期间)严格调控信号来调节不同的结果。重要的是，GFS在进化上高度保守，使得来自动物模型的信息对人类神经科学来说是有信息的。神经科学中的一个主要挑战是了解大脑如何长时间获取和存储信息，以及这些长期记忆(LTM)如何变得容易受到神经疾病和神经退行性疾病的影响。GF是LTM所必需的，但目前尚不清楚每个家族对LTM形成的独特贡献。我的工作将直接探索这一假设，即不同的GF家族不仅参与时空协调的信号通路，诱导不同的基因表达谱，而且还协同作用介导LTM的形成。这 该项目旨在通过使用模式生物Aplysia calfornica来检验几个假设，这是一个强大的系统，用于阐明与适应行为变化相关的分子机制的时空协调。我将重点介绍两个GF家族：神经营养因子通过原肌素相关激酶B受体(TrkB)和转化生长因子超家族通过转化生长因子受体II(TGF？R-II)传递信号。首先，我将检验这样一个假设，即不同的GF家族参与时空调控的信号级联反应，从而诱导不同的基因表达谱。为了测试这一概念，我将使用受体体嵌合体在TrkB或TGF？R-II信号转导系统中 在模拟形式的LTM训练过程中或之后，检查胞体或突触，然后确定LTM所需的蛋白质--丝裂原活化蛋白激酶(MAPK)的激活是否受到抑制。使用相同的方法，我将确定LTM形成所需的进化保守基因C/EBP、Uch、Kinesin和Neuresin的表达是否被阻断GF信号所阻断。其次，我将通过(I)在LTM训练期间或之后在胞体和/或突触阻断GF信号来确定LTM的行为表达是否需要时空调节的GF信号，以及(Ii)测试GF信号是否协同作用来支持LTM的形成，来探索在分子水平上观察到的行为相关性。这个整体项目将提供对LTM形成过程中的GF信号的更好的理解。阐明生长因子信号转导的机制将从基础科学的角度为该领域提供信息，并可能为与神经疾病和相关疾病相关的治疗靶点提供临床相关的假说。

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.