The Role of PKMzeta in Memory Destabilization and Reconsolidation

PKMzeta 在记忆不稳定和再巩固中的作用

• 批准号: RGPIN-2017-05140
• 负责人: Nader, Karim
• 金额: $ 2.84万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660572
• 关键词: Role; PKMzeta; Memory; Destabilization; Reconsolidation

The study of memory has come a long way in identifying important molecules in the brain necessary for learning and maintaining long-term memories. One such molecule is the protein PKMzeta which is crucial for maintaining memories over time. What is unclear, however, is how PKMzeta and its memory maintenance process copes with rapid changes to memory. For instance, when certain stored (stable) memories are recalled, they become temporarily unstable only to be re-stabilized shortly thereafter. How memories destabilize on the cellular level is largely unclear but it seems likely that changes to PKMzeta may be responsible. This research will investigate the role of PKMzeta in memory destabilization and re-stabilization (or “reconsolidation”). To do so, we will use biochemistry techniques to study and manipulate auditory fear memories in rats at the protein level. Specifically, these are memories in which a rat learns that a tone predicts a footstock and subsequently shows fear behavior (“freezing”) when the tone is played. ***Evidence suggests that a decrease in the quantity of PKMzeta seems to coincide with memory destabilization. We will therefore test if production of new PKMzeta is necessary to re-stabilize the memory by blocking production of this protein specifically while the memory is destabilized. We will also test if memory destabilization requires a decrease in the quantity of PKMzeta to occur. We will compare levels of PKMzeta after recall of memories that do or do not destabilize. We will also determine if artificially increasing the amount of PKMzeta in the brain prevents destabilization. Thirdly we will test if artificially decreasing PKMzeta renders memories destabilized. We will use these results to further investigate the unique properties of strong, destabilization-resilient memories. Lastly, we will study if learning causes a specific change to the PKMzeta gene which enables it to maintain memories before, after, and even during destabilization. We expect our experiments to reveal an integral role for PKMzeta not only in maintaining memories but also throughout memory destabilization and re-stabilization.***This research will help to bridge different fields of memory together in order to understand the common processes that underpin them. In doing so, we will be able to answer fundamental questions about how the brain stores memories and how memories manage to survive in an ever-changing brain.

记忆的研究在识别大脑中学习和维持长期记忆所必需的重要分子方面取得了很大进展。其中一种分子是蛋白质PKMzeta，它对随着时间的推移维持记忆至关重要。然而，目前尚不清楚的是，PKMzeta及其记忆维持过程如何应对记忆的快速变化。例如，当某些储存的（稳定的）记忆被唤起时，它们会暂时变得不稳定，然后很快就会重新稳定下来。记忆是如何在细胞水平上不稳定的还很不清楚，但似乎PKMzeta的变化可能是负责的。本研究将探讨PKMzeta在记忆不稳定和重新稳定（或“重新巩固”）中的作用。为此，我们将使用生物化学技术在蛋白质水平上研究和操纵大鼠的听觉恐惧记忆。具体地说，这些记忆中，老鼠学习到一个音调预测一个踏板，随后显示出恐惧行为（“冻结”）时，音调播放。* 证据表明，PKMzeta数量的减少似乎与记忆不稳定相一致。因此，我们将测试新PKMzeta的产生是否是通过在记忆不稳定时特异性地阻断这种蛋白质的产生来重新稳定记忆所必需的。我们还将测试记忆不稳定是否需要PKMzeta数量的减少。我们将在回忆起不稳定或不稳定的记忆后比较PKMzeta的水平。我们还将确定人工增加大脑中PKMzeta的数量是否可以防止不稳定。第三，我们将测试是否人为降低PKMzeta会使记忆不稳定。我们将利用这些结果来进一步研究强大的，不稳定的弹性记忆的独特属性。最后，我们将研究学习是否会引起PKMzeta基因的特定变化，使其能够在不稳定之前，之后甚至在不稳定期间保持记忆。我们希望我们的实验能够揭示PKMzeta不仅在维持记忆方面，而且在记忆不稳定和重新稳定过程中发挥着不可或缺的作用。*这项研究将有助于将不同的记忆领域连接在一起，以了解支撑它们的共同过程。通过这样做，我们将能够回答有关大脑如何存储记忆以及记忆如何在不断变化的大脑中生存的基本问题。