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

描述（由申请人提供）：生长因子（GF）是一种分泌型分子，对发育过程中可塑性的许多方面都很重要，包括轴突生长、肌动蛋白细胞骨架重排和突触形成。有多个家庭的生长因子，如神经营养因子和转化生长因子？(TGF?)超家族，其在发育期间通过在空间（例如，在细胞体处与在突触处）和时间（例如，在突触形成期间与在突触稳定期间）两者中紧密调节的信号传导来介导不同的结果。重要的是，GF在进化上高度保守，使得来自动物模型的信息为人类神经科学提供了信息。神经科学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系统疾病和神经退行性疾病的影响。GF是LTM所需的，但不知道GF每个家族如何独特地促进LTM形成。我的工作将直接探讨这一假设，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，而且还协同相互作用，介导LTM的形成。这 该项目的目的是通过使用模式生物加州滨藜来测试几个假设，加州滨藜是一个强大的系统，用于阐明与适应性行为变化相关的分子机制的时空协调。我将集中在两个GF家族：神经营养因子信号通过原溶酶相关激酶B受体（Trk B）和TGF超家族信号通过TGF受体II（TGF？r-II）。首先，我将测试的假设，不同的GF家族从事时空调节信号级联，诱导不同的基因表达谱。为了测试这个概念，我将阻止TrkB或TGF？使用受体体嵌合体的r-II信号传导 索马或突触，然后确定是否有丝分裂原活化蛋白激酶（MAPK）活化（LTM所需的蛋白质）被抑制。使用相同的方法，我将确定是否通过阻断GF信号传导来阻断LTM形成所需的进化保守基因C/EBP、Uch、驱动蛋白和neurexin的表达。第二，我将探索行为相关性的观察来自在分子水平上（i）阻断GF信号在索马和/或突触，在LTM训练期间或之后，以确定是否行为的LTM表达需要时空调节的GF信号，和（ii）测试是否GF信号级联协同相互作用，以利于LTM的形成。这个整体项目将提供一个更好的了解在LTM形成过程中的GF信号。阐明GF信号传导的机制将从基础科学的角度为该领域提供信息，并可能为神经系统疾病和相关疾病的治疗靶点提供临床相关假设。

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.