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 形成大脑中持久的身体所需的编排。 必须在精确时间点集成的分子过程的复杂网络才能创建纤维素 有利于长期记忆（LTM）的象征。 LTM形成期间的信号级联的精确时机仍然是一个完全理解的 计算的分子过程有助于LTM形成的时间要求是生长因子（GF） 信号传导。 作为成人的突触塑料和记忆的关键介体。 特定的GF，转化生长因子β（TGFβ），提供了独特的机制，在 ltm的时间处理。 级联可以通过IS活动的整合充当“分子计时器”，从而有助于时间 LTM形成所需的计算。 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了LTM形成所需的时间处理。 在目标I中，我将研究TGFβ-配体的合成和/或释放如何可能发生的事件，其事件的事件是其倾斜的倾斜度倾斜的， 在AIM II中是LTM形成所必需的，我将通过蛋白水解研究 在TGFβ受体的水平上的变化可能是关键的时间保存事件。 TGFβ实用的细胞内单蛋白是否对所有人的LTM形成都是必要的 实验，我将使用强大的范式来研究海洋软体动物的LTM 范式仅在两次试验后诱导LTM进行敏化，而仅当试验被特定的特定时 高度解释的时间窗口为45分钟。 从重复的刺激（试验2），提供对特定时间上的相互作用的未平行访问 底层LTM的基础。 观点，因为这些发现将对理解人类记忆形成有直接的影响 健康状况以及在神经系统疾病中受到损害。 与这些神经学疾病的发病机理有关，了解何时和温暖 记忆形成期间大脑中的行为可以提供新的途径，以发展更有效和有效 有针对性的治疗学。