Significance of Protein Synthesis by the Integrated Stress Response in Neuromodulatory Neurons for Adaptive Behavior and Synaptic Plasticity

摘要 可塑性机制赋予大脑巨大的能力来适应广泛的经验和 曝光。蛋白质合成，包括局部的突触，是许多形式突触所必需的 可塑性。整合应激反应(ISR)是一种高度保守的生化途径，调节 蛋白质合成。ISR显著改变了哪些蛋白质是通过磷酸化启动因子而形成的， EIF2阿尔法。ISR的命名是因为它对全身的影响--它提供细胞应激反应 机制。然而，在大脑中，ISR也被发现是突触可塑性的有效修饰物， 学习和记忆。在高水平的总结中，正常大脑中的ISR抑制已被证明是较低的 在一些疾病环境中，实例化长期记忆所需的经验阈值，例如 创伤性脑损伤，它可以挽救认知行为缺陷。从机制上讲，抑制ISR的操作 与长时间增强(LTP)有关；而ISR激活对于 突触抑制(LTD)。 在试图了解ISR如何导致痴呆症和肌张力障碍等疾病时，我们认识到 对大脑ISR活动的基本理解上的主要差距，包括它正常的时间和地点 激活了。因此，我们开发了一种全脑病毒式记者Spotlight，它为ISR提供双色读数 激活状态。利用聚光灯，我们揭示了大脑中ISR的一种完全非规范的模式- 涉及其影响的一类神经元(纹状体胆碱能中间神经元)的结构性激活 多巴胺能调节它们的放电反应。此外，这些细胞中的细胞自主ISR抑制 重述了先前通过系统操作观察到的“学习增强”效果。这些发现 要么颠覆或至少大幅增加ISR在可塑性、学习和记忆方面的工作模式。 在这里，我们建议进一步了解ISR如何在大脑中作用于神经调节、突触 可塑性、学习和记忆。我们将重点关注3个知识差距：(1)ISR在多大程度上采取行动 神经调节细胞，而不是在经历可塑性的局部突触，解释ISR对突触的影响 可塑性和行为？(2)ISR通过什么分子机制改变多巴胺(D2R) 胆碱能神经元的信号转导结果？以及(3)新的ISR记者能否通过 需要时空分辨率来解决ISR何时何地激活蛋白质合成 突触可塑性条件？我们预计这项工作的结果将影响普通细胞生物学 ISR靶向治疗的原理和特定纹状体机制及其翻译相关性 正在进行的努力。

ABSTRACT Plasticity mechanisms endow the brain with immense capacity to adapt to a wide range of experience and exposures. Protein synthesis, including locally at synapses, is a requirement for many forms of synaptic plasticity. The Integrated Stress Response, ISR, is a highly conserved biochemical pathway that regulates protein synthesis. The ISR markedly shifts which proteins are made by phosphorylating the initiation factor, eIF2alpha. The ISR was named for its effects body-wide - in which it provides a cell stress response mechanism. However, in the brain, the ISR has also been found to be a potent modifier of synaptic plasticity, learning and memory. At a high level of summary, ISR inhibition in the normal brain has been shown to lower the thresholds of experience needed to instantiate long-lasting memory and in some disease settings, such as traumatic brain injury, it rescues cognitive behavioral deficits. Mechanistically, ISR-inhibiting manipulations have been associated with long-lasting potentiation (LTP); while ISR activation is necessary for forms of synaptic depression (LTD). While trying to understand how the ISR contributes to diseases like dementia and dystonia, we recognized major gaps in the basic understanding of brain ISR actions, including when and where it was normally activated. We therefore developed a brain-wide viral reporter, SPOTlight, that gives a two-color readout for ISR activation state. Using SPOTlight, we uncovered a wholly non-canonical modality for the ISR in the brain – involving its constitutive activation in a class of neurons (striatal cholinergic interneurons) where it influences dopaminergic modulation of their firing response. Additionally, cell autonomous ISR inhibition in these cells recapitulated previous “learning enhancement” effects observed with systemic manipulations. These findings either upend, or at least substantially add to, working models for the ISR in plasticity, learning and memory. Here, we propose to advance understanding of how the ISR acts in the brain for neuromodulation, synaptic plasticity, learning and memory. We will focus on 3 knowledge gaps: (1) To what extent does ISR action in neuromodulatory cells, instead of at local synapses undergoing plasticity, explain ISR effects on synaptic plasticity and behavior? (2) What are the molecular mechanisms by which the ISR changes dopamine (D2R) signal transduction outcomes in cholinergic neurons? and (3) Can new ISR reporters be developed with the spatiotemporal resolution needed to resolve when and where the ISR activates protein synthesis under synaptic plasticity conditions? We expect the outcomes of this work to impact both general cell biological principles and specific striatal mechanisms and to have translational relevance for ISR-targeting therapeutic efforts that are underway.