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

TGFbeta 的处理作为长期记忆形成中精确时间编排的机制

• 批准号: 10490826
• 负责人: Paige Miranda
• 金额: $ 3.14万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490826
• 关键词: Adult; Afferent Neurons; Animal Model; Aplysia; Behavioral; Binding; Biological Assay; Biological Models; Brain; CREBBP gene; CRISPR/Cas technology; Clinical; Complex; Deposition; Development; Electrophysiology (science); Elements; Environment; Event; Extracellular Matrix; Family; Ganglia; Gene Expression; Goals; Growth Factor; Heart; Human; Immediate-Early Genes; Individual; Knock-out; Laboratories; Lead; Learning; Ligands; Longitudinal Studies; Mammals; Mediating; Mediator of activation protein; Memory; Modernization; Molecular; Monitor; Neuraxis; Neurobiology; Neurodegenerative Disorders; Neurosciences; Nuclear; Pathogenesis; Pattern; Play; Positioning Attribute; Preparation; Process; Production; Property; Proteins; Proteolysis; Regulation; Role; Signal Transduction; Smad Proteins; Specificity; Stimulus; Structure; Synaptic plasticity; System; TGF beta type III receptor; Testing; Time; Training; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; analog; developmental plasticity; experimental study; immunocytochemistry; long term memory; nervous system disorder; novel; presynaptic; response; targeted treatment; transcription factor

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.

项目摘要 现代神经科学的巨大挑战之一是了解详细的分子 形成大脑持久记忆所需的编舞。这个挑战的核心是 必须在精确时间点集成的分子过程的复杂网络才能创建细胞 有利于长期记忆（LTM）形成的环境。但是，神经生物学过程和 LTM形成过程中其信号级联的精确时机尚待充分理解。一个家庭 可能有助于LTM形成的临时要求的分子过程是生长因子（GF） 信号。 GFS，被视为发育可塑性的调节剂，被广泛赞赏 作为成人突触可塑性和记忆的关键介体。我们实验室的最新发现表明 特定的GF，转化生长因子β（TGFβ），提供了独特的机制，在 LTM的临时处理。该项目将测试TGFβ信号传导的新假设 级联可以通过其活动的整合充当“分子计时器”，从而有助于临时 LTM形成所需的计算。为此，我将检查TGFβ的三个不同组成部分 LTM期间的信号传导级联反应：（i）TGFβ-rigands，（ii）TGFβ受体和（iii）下游介质蛋白，至 确定每个组件如何唯一贡献LTM形成所需的临时处理。 在AIM I中，我将检查TGFβ-配体的合成和/或释放如何是关键事件 LTM形成是必需的。在AIM II中，我将研究TGFβ配体激活，蛋白水解和 TGFβ受体水平的变化可能是关键的时间保存事件。最后，在AIM III中，我将评估 LTM形成是否需要通过SMAD蛋白通过TGFβ引起的细胞内单单。所有人 实验，我将使用开发的强大范式来研究海洋软体动物中的LTM。这 范式仅在两次试验后引起LTM的灵敏度，但前提 高度约束的时间窗口为45分钟。这个最小的系统将发射刺激分开（试验1） 从重复的刺激（试验2），提供对特定临时相互作用的无与伦比的访问 基础LTM组。最后，该项目有潜力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形成的直接影响 健康状况以及在神经系统疾病中受到损害时。由于TGFβ的信号传导级联一直是 在许多此类神经系统疾病的发病机理中实施，了解TGFβ何时以及如何 记忆形成过程中大脑中的行为可以为发展更有效和 靶向疗法。