PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.
PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.
复制标题
DOI：
10.1371/journal.pbio.0060318
复制
发表时间：
2008-12-23
期刊：
影响因子：
9.8
通讯作者：
Fenton, Andre A.
中科院分区：
文献类型：
--
作者：
Serrano, Peter;Friedman, Eugenia L.;Kenney, Jana;Taubenfeld, Stephen M.;Zimmerman, Joshua M.;Hanna, John;Alberini, Cristina;Kelley, Ann E.;Maren, Stephen;Rudy, Jerry W.;Yin, Jerry C. P.;Sacktor, Todd C.;Fenton, Andre A.
长期记忆是如何储存的是神经科学中的一个基本问题。大脑长期记忆储存的第一个分子机制最近被确定为蛋白激酶Mzeta （PKMζ）的持续作用，这是一种自主活性的非典型蛋白激酶C （PKC）异构体，对维持长期增强（LTP）至关重要。PKMζ维持着不良的条件关联，但是这种激酶在大脑中编码的信息的一般形式是什么是未知的。我们首先证实了zeta抑制肽（ZIP）的作用特异性，通过用chelerythrine （PKMζ活性的第二种抑制剂）破坏长期记忆来主动回避位置。然后，我们使用ZIP检查了PKMζ在背侧海马（DH）和基底外侧杏仁核（BLA）的抑制对在桡臂迷宫、水迷宫、抑制性回避以及情境和线索恐惧条件反射范式中获得的一维旧信息保留的影响。在DH中，PKMζ抑制选择性地破坏了空间参考信息的保留，但对桡臂迷宫的空间工作记忆没有影响，对水迷宫的精确空间信息没有影响。因此，保留准确的空间信息，而不是程序和上下文信息需要PKMζ活动。同样，海马体中的PKMζ抑制不影响恐惧条件反射后的情境信息。相比之下，BLA中的PKMζ抑制损害了情境恐惧和听觉恐惧的经典条件刺激-非条件刺激（CS-US）关联的保留，以及工具性条件抑制回避。PKMζ抑制对休克后冻结无影响，表明BLA介导的恐惧表达保持完整。因此，持久的PKMζ活动是一种普遍的机制，对于特定的、准确的学习信息的食欲和厌恶动机的保留，但对于处理上下文的、不精确的或程序性的信息并不需要。长期记忆如何以物理痕迹的形式储存在大脑中是神经科学的一个基本问题。最近，我们首次发现了长期记忆储存的分子机制。我们发现，不愉快的记忆是通过一种酶的持续作用储存起来的，这种酶是一种蛋白激酶C，被称为PKMζ，因为这些记忆可以通过向大脑中注射PKMζ抑制剂而迅速消除。但是大脑中所有形式的记忆和信息都是由PKMζ储存的吗？在这里，我们首先用PKMζ的第二种抑制剂证实，海马体（大脑中存储空间信息的关键区域）中不愉快的长期记忆被迅速抹去。然后我们检查了储存在海马体和基底外侧杏仁核中的其他记忆，基底外侧杏仁核是另一个对情绪记忆至关重要的区域。我们测试了对特定地点的记忆，包括不愉快的和有益的，对一般背景信息的记忆，声音和可怕事件之间的联系，就像巴甫洛夫研究的那样，以及对特定行为的记忆。我们发现PKMζ存储特定的关联，包括不愉快的和有益的，地点，事件和行动，因此是大脑记忆存储的一般机制。一种名为PKMζ的大脑酶的持续活动，储存了对地点、事件和行为的特定联想，包括不愉快的和有益的，因此是记忆储存的一般机制。
How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMζ activity. We then examined, using ZIP, the effect of PKMζ inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMζ inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ inhibition in the BLA impaired retention of classical conditioned stimulus–unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information. How long-term memories are stored as physical traces in the brain is a fundamental question in neuroscience. Recently, we discovered the first molecular mechanism of long-term memory storage. We showed that unpleasant memories are stored by the persistent action of an enzyme, a form of protein kinase C, termed PKMζ, because these memories can be rapidly erased by injecting a PKMζ inhibitor into the brain. But are all forms of memory and information in the brain stored by PKMζ? Here, we first confirmed with a second inhibitor of PKMζ that unpleasant long-term memories in the hippocampus, a region of the brain critical for storing spatial information, are rapidly erased. We then examined other memories stored in the hippocampus and the basolateral amygdala, another region critical for emotional memories. We tested memories for specific places, both unpleasant and rewarding, memories for general background information, associations between a sound and a fearful event, like that studied by Pavlov, and memories for performing a specific action. We found that PKMζ stores specific associations, both unpleasant and rewarding, for places, events, and actions, and is thus a general mechanism for memory storage in the brain. The persistent activity of a brain enzyme, PKMζ, stores specific associations, both unpleasant and rewarding, for places, events, and actions, and is thus a general mechanism for memory storage.
登录
查看更多内容
影响因子：
6.1
作者：
Lim, Seyoung;Choi, Jung Woong;Suh, Pann-Ghill
通讯作者：
Suh, Pann-Ghill
影响因子：
56.9
作者：
Fyhn, M;Molden, S;Moser, MB
通讯作者：
Moser, MB
影响因子：
3.3
作者：
Andrzejewski, ME;Spencer, RC;Kelley, AE
通讯作者：
Kelley, AE
影响因子：
2.5
作者：
Cimadevilla, JM;Fenton, AA;Bures, J
通讯作者：
Bures, J
影响因子：
2
作者：
Milekic, Maria H.;Pollonini, Gabriella;Alberini, Cristina M.
通讯作者：
Alberini, Cristina M.