The role of protein kinase Mzeta in hippocampal-dependent memory maintenance.

蛋白激酶 Mzeta 在海马依赖性记忆维持中的作用。

• 批准号: 8059965
• 负责人: JANINE LYNN KWAPIS
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059965
• 关键词: Address; Amygdaloid structure; Animals; Bilateral; Biological; Brain; Cannulas; Catalytic Domain; Complex; Conditioned Stimulus; Cues; Dorsal; Elements; Episodic memory; Fright; Goals; Hippocampus (Brain); Human; Injection of therapeutic agent; Knowledge; Learning; Literature; Long-Term Potentiation; Maintenance; Memory; Memory Disorders; Microinjections; Molecular; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Play; Process; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein Kinase Inhibitors; Radial; Rattus; Research; Rewards; Role; Stimulus; Structure; Sucrose; Synapses; Taste Perception; Testing; Time; Training; Translating; Work; analog; arm; base; conditioned fear; conditioning; improved; inhibitor/antagonist; long term memory; prevent; procedural memory; protein kinase inhibitor; public health relevance; relational memory; research study; therapy development; way finding

DESCRIPTION (provided by applicant): The broad goal of the proposed project is to understand how long-term memories are stored in the brain through the activity of protein kinase Mzeta (PKM?). Using rats, this project will determine the specific subset of hippocampal-dependent associations that require PKM? activity for maintenance to better understand PKM? requirements in the brain. Three specific aims will be addressed. The first aim is to determine whether PKM? activity is differentially required in the hippocampus and amygdala to maintain aversive, contextually-based memories. To achieve this aim, trace fear conditioning (TFC) will be used to create an aversive context-based memory that requires both the hippocampus and amygdala for acquisition (1,2). In TFC, a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US) with an empty trace period separating the two stimuli. The second aim, which addresses whether appetitive spatial memory requires hippocampal PKM? activity, will be achieved using the spatially-based 8-arm radial arm maze task. In the radial arm maze task, rats must use spatial cues to determine which 4 of the 8 available arms contain hidden sucrose pellets. This task requires the hippocampus for acquisition and relies on external spatial cues in the training room, rather than contextual cues present within the apparatus (3). The final aim is to determine whether different requirements exist for hippocampal PKM? activity in the maintenance of spatial and contextual appetitive memory associations. To achieve this goal, the place conditioning task will be used to create a hippocampal- dependent appetitive context memory that can be directly compared with the spatial radial arm maze memory used in aim 2. In place conditioning, sucrose pellets are repeatedly available in one context while no reward is provided in a second context, leading the animal to prefer the sucrose-paired context in a subsequent test (40). In order to test the requirement for hippocampal PKM? activity in each of these forms of memory, a specific, potent inhibitor of PKM? activity called ?-pseudosubstrate inhibitory peptide (ZIP) will be locally microinjected into the dorsal hippocampus or amygdala during the storage phase of each memory (5). Animals will be prepared with bilateral cannulae aimed at the appropriate structure to allow for restricted, local injection of the drug. This set of experiments will elucidate whether PKM? is required to maintain a broad set of hippocampal- dependent memories or whether it only maintains an exclusive subset of memories that require the hippocampus for acquisition. This research has important implications for both improving memory storage and disrupting maladaptive memory storage in human patients. PUBLIC HEALTH RELEVANCE: This project will expand the current literature on the physiological underpinnings of long-term memory storage. Enhanced understanding of the biological mechanisms underlying memory maintenance is necessary not only to increase our basic knowledge of this process, but also to potentially translate research findings to both normal and disordered memory in humans.

描述（由申请人提供）：拟议项目的总体目标是了解长期记忆如何通过蛋白激酶 Mzeta（PKM？）的活性存储在大脑中。该项目将使用大鼠来确定需要 PKM 的海马依赖性关联的特定子集？进行维护活动以更好地了解 PKM？对大脑的要求。将解决三个具体目标。第一个目的是确定是否PKM？海马体和杏仁核需要不同的活动来维持厌恶的、基于情境的记忆。为了实现这一目标，追踪恐惧条件反射 (TFC) 将用于创建基于厌恶情境的记忆，需要海马体和杏仁核来获取 (1,2)。在 TFC 中，中性条件刺激 (CS) 与厌恶性非条件刺激 (US) 配对，两个刺激之间有一个空跟踪周期。第二个目标是解决食欲空间记忆是否需要海马 PKM？活动，将使用基于空间的 8 臂径向臂迷宫任务来实现。在径向臂迷宫任务中，大鼠必须使用空间线索来确定 8 个可用臂中的哪 4 个包含隐藏的蔗糖颗粒。这项任务需要海马体进行采集，并依赖于训练室中的外部空间线索，而不是设备内存在的上下文线索 (3)。最终目的是确定海马PKM是否存在不同的要求？维持空间和情境食欲记忆关联的活动。为了实现这一目标，地点条件反射任务将用于创建海马依赖性食欲上下文记忆，该记忆可以直接与目标 2 中使用的空间径向臂迷宫记忆进行比较。就地条件反射任务，蔗糖颗粒在一个上下文中重复可用虽然在第二个环境中没有提供奖励，但导致动物在随后的测试中更喜欢蔗糖配对的环境 (40)。为了测试海马PKM的要求？每种记忆形式的活性，PKM 的特异性、有效抑制剂？在每个记忆的储存阶段，称为β-伪底物抑制肽（ZIP）的活性将被局部显微注射到背侧海马或杏仁核中（5）。动物将准备好双侧插管，以适当的结构进行限制性局部注射药物。 这组实验将阐明PKM是否存在？是否需要维持广泛的海马依赖性记忆，或者是否仅维持需要海马体获取的记忆的专有子集。这项研究对于改善人类患者的记忆存储和破坏适应不良的记忆存储具有重要意义。 公共健康相关性：该项目将扩展有关长期记忆存储生理基础的现有文献。加强对记忆维持生物学机制的理解不仅有助于增加我们对这一过程的基础知识，而且有可能将研究结果转化为人类正常和紊乱的记忆。