Processing of TGFbeta as a mechanism for precise temporal orchestration in long term memory formation

项目总结 现代神经科学的最大挑战之一是理解详细的分子 在大脑中形成持久记忆所需的编舞。这一挑战的核心是 分子过程的复杂网络，必须在精确的时间点整合才能创建细胞 有利于长时记忆形成的环境。然而，神经生物学过程和 它们在LTM形成过程中信号级联的准确时间仍有待完全了解。一个家庭 可能有助于LTM形成的时间需求的分子过程是生长因子(GF) 发信号。GFS被公认为发育可塑性的调节器，正受到广泛的赞赏 作为成人突触可塑性和记忆的关键媒介。我们实验室的最新发现表明， 转化生长因子β(转化生长因子β)是一种特殊的生长因子，它在血管生成中起重要作用 LTM背后的时间加工。该项目将检验新的假设，即转化生长因子β的S信号 CASCADE通过其活动的整合，可以起到分子计时器的作用，有助于时间 LTM形成所需的计算。为此，我将研究转化生长因子β的三个不同的组成部分。 LTM过程中的信号级联：(I)转化生长因子β配体，(Ii)转化生长因子β受体，和(Iii)下游介质蛋白，以 确定每个分量如何唯一地对LTM形成所需的时间处理作出贡献。 在目标一中，我将研究转化生长因子β配体的合成和/或释放如何成为关键事件 对于LTM的形成是必要的。在AIM II中，我将研究转化生长因子β配体是如何通过蛋白分解和 转化生长因子β受体水平的变化可能是重要的计时事件。最后，在第三个目标中，我将评估 转化生长因子β通过Smad蛋白启动的细胞内信号转导是否对LTM的形成是必需的。为所有人 实验中，我将用一个强大的研究范式来研究海洋软体动物海兔中的LTM。这 范式仅在两次试验后诱导LTM致敏，但只有在试验被特定的、 高度受限的时间窗口为45分钟。这个最小的系统将启动刺激分开(试验1) 来自重复刺激(试验2)，提供对特定时间交互的无与伦比的访问 下伏的LTM地层。最后，这个项目有可能从临床上产生重大影响 观点，因为这些发现将对理解人类记忆的形成有直接的影响 在健康的条件下，以及在神经系统疾病中受到损害时。自从转化生长因子β的S信号级联以来， 与许多神经疾病的发病机制有关，了解转化生长因子β的时间和方式 大脑在记忆形成过程中的行为可以提供新的途径，以发展更有效和 靶向治疗。

PROJECT SUMMARY One of the great challenges of modern neuroscience is understanding the detailed molecular choreography required for the formation of lasting memories in the brain. At the heart of this challenge lies a complex network of molecular processes that must be integrated at precise timepoints to create a cellular environment favorable for long-term memory (LTM) formation. However, the neurobiological processes and the precise timing of their signaling cascades during LTM formation remain to be fully understood. One family of molecular processes that could contribute to the temporal requirements for LTM formation is growth factor (GF) signaling. GFs, canonically viewed as regulators of developmental plasticity, are becoming widely appreciated as key mediators of synaptic plasticity and memory in adults. Recent findings from our laboratory show that a specific GF, transforming growth factor beta (TGFβ), provides a unique mechanism that plays a major role in the temporal processing underlying LTM. This project will test the novel hypothesis that TGFβ’s signaling cascade can act as a “molecular timekeeper” through the integration of its activity, contributing to the temporal computations necessary for LTM formation. To this end, I will examine three distinct components of the TGFβ signaling cascade during LTM: (i) TGFβ-ligands, (ii) TGFβ-receptors, and (iii) downstream mediator proteins, to determine how each component uniquely contributes to the temporal processing necessary for LTM formation. In Aim I, I will examine how synthesis and/or release of TGFβ-ligands could each be key events whose timing is necessary for LTM formation. In Aim II, I will study how TGFβ ligand activation, through proteolysis and changes at the level of TGFβ-receptors, may be critical time-keeping events. Finally, in Aim III, I will assess whether TGFβ-initiated intracellular singling via Smad proteins is necessary for LTM formation. For all experiments, I will use a powerful paradigm developed to study LTM in the marine mollusk Aplysia. This paradigm induces LTM for sensitization after only two trials, but only if the trials are separated by a specific, highly constrained time window of 45 minutes. This minimal system separates the initiating stimulus (Trial 1) from the repeated stimulus (Trial 2), providing unparalleled access to the specific temporal interactions underlying LTM formation. Finally, this project has the potential to contribute significant impact from a clinical perspective, as these findings will have direct implications for understanding human memory formation under healthy conditions and when compromised in neurological disease. Since TGFβ’s signaling cascade has been implicated in the pathogenesis of many of these neurological disorders, understanding when and how TGFβ acts in the brain during memory formation could provide novel avenues for developing more effective and targeted therapeutics.