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 现代神经科学面临的最大挑战之一是了解 这是大脑中形成持久记忆所需的编排。这一挑战的核心在于 分子过程的复杂网络，必须在精确的时间点整合，以创建细胞 有利于长期记忆（LTM）形成的环境。然而，神经生物学过程和 在LTM形成过程中它们的信号级联的精确定时仍有待完全理解。One系列 可能有助于LTM形成的时间要求的分子过程是生长因子（GF） 发信号。生长因子被公认为发育可塑性的调节因子， 作为成年人突触可塑性和记忆的关键介质。我们实验室最近的研究结果表明， 特异性GF，即转化生长因子β（TGFβ），提供了一种独特的机制， LTM下的时间处理。该项目将测试新的假设，即TGFβ的信号转导 级联可以作为一个“分子计时器”，通过整合其活动，有助于时间的 计算所需的LTM形成。为此，我将研究TGFβ的三种不同成分， LTM期间的信号级联：（i）TGFβ-配体，（ii）TGFβ-受体，和（iii）下游介体蛋白， 确定每个组件如何独特地有助于LTM形成所需的时间处理。 在目的I中，我将研究TGFβ-配体的合成和/或释放如何成为关键事件， 是LTM形成所必需的。在目的II中，我将研究如何TGFβ配体活化，通过蛋白水解， TGFβ受体水平的变化可能是关键的计时事件。最后，在目标III中，我将评估 TGFβ通过Smad蛋白启动的细胞内信号转导是否是LTM形成所必需的。为所有 实验中，我将使用一个强大的范例开发研究LTM在海洋软体动物Aaclasia。这 范例仅在两次试验后诱导LTM致敏，但仅当试验被特定的， 45分钟的高度受限的时间窗口。这个最小的系统分离了初始刺激（试验1） 从重复的刺激（试验2），提供了无与伦比的访问特定的时间相互作用 潜在的LTM形成。最后，该项目有可能从临床上产生重大影响。 因为这些发现将对理解人类记忆的形成产生直接影响。 健康状况和神经系统疾病时。由于TGFβ的信号级联已经被 与许多神经系统疾病的发病机制有关，了解TGFβ何时以及如何 大脑在记忆形成过程中的作用可以为开发更有效， 靶向治疗。