Multiple memory networks: plasticity mechanisms, representations, and behaviour

多重记忆网络：可塑性机制、表征和行为

• 批准号: RGPIN-2020-06929
• 负责人: McDonald, Robert
• 金额: $ 4.74万
• 依托单位: University of Lethbridge
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741498
• 关键词: Multiple; memory; networks; plasticity; mechanisms

Empirical and theoretical work suggests that the organization of memory in the mammalian brain and the neural systems that mediate them play a pivotal role in our thoughts, emotions, choices, actions, and our personalities. The theory guiding this research program is that memory function in the mammalian brain is organized into groups of neural networks mediating different memory functions. Within this organization, normal thought and behaviour arise from cooperative and competitive interactions between these different systems.      For this proposal we focus on the functions of a memory network centered on the hippocampus (HPC) and associated plasticity mechanisms. This work emerged from controversies over the role of N- methyl-D-aspartic acid (NMDAR) mediated long-term potentiation (LTP) in the acquisition of spatial information during training on the Morris water task (MWT). Seminal behavioural pharmacology work showed that NMDAR LTP was necessary for acquisition of the MWT but not expression. However, later research revealed that spatial learning in the MWT is rendered NMDAR independent when pre-training is employed.      We developed a behavioural paradigm in an attempt to understand why NMDAR-mediated plasticity mechanisms are involved in some variants of place learning and not others. The pattern of effects led us to several hypotheses about the role of HPC NMDAR in spatial learning. HYPOTHESIS: HPC representations formed during rapid new learning using familiar or new spatial information will differ in content and underlying neurobiological mechanism. New learning with familiar information will induce rate remapping processes that are not NMDAR dependent, while new learning with new information will induce global remapping. Rate remapping can be supported by non-NMDA forms of LTP mediated by voltage-gated calcium channels (VGCC) while global remapping requires both forms of plasticity. We will use electrophysiology, imaging, behavioural pharmacology, and immunohistochemistry techniques to assess how HPC representations will differ when learning uses familiar vs. new spatial information.      IMPACT: There has been significant efforts aiming to account for how behaviour is shaped by exposure to specific events, the neural networks responsible, and the biochemical mechanisms supporting these functions. Understanding how the HPC represents different experiences used by individuals to navigate a complex world and the underlying neurobiological mechanisms supporting these functions is fundamental to understand the underpinnings of normal and abnormal manifestations of behaviour. This work will further our understanding of the nature and causes of psychiatric disorders including addiction, anxiety, post-traumatic stress disorder, and obesity. We seek to provide key information about when HPC NMDAR-mediated LTP is required for learning in the mammal as there is still significant room for discovery, innovation, and impact in this area.

经验和理论研究表明，哺乳动物大脑中的记忆组织和调节它们的神经系统在我们的思想、情感、选择、行动和个性中起着关键作用。指导这项研究计划的理论是，哺乳动物大脑中的记忆功能被组织成调节不同记忆功能的神经网络组。在这个组织中，正常的思想和行为来自这些不同系统之间的合作和竞争互动。 对于这个建议，我们专注于以海马（HPC）为中心的记忆网络的功能和相关的可塑性机制。这项工作出现的争议的作用N-甲基-D-天冬氨酸（NMDAR）介导的长时程增强（LTP）的空间信息的获取在训练期间的Morris水任务（MWT）。精液行为药理学研究表明，NMDAR LTP是必要的收购MWT，但不表达。然而，后来的研究表明，在MWT的空间学习呈现NMDAR独立时，采用预训练。 我们开发了一个行为范式，试图了解为什么NMDAR介导的可塑性机制参与了一些变体的地方学习，而不是其他。这种效应模式使我们对HPC NMDAR在空间学习中的作用提出了几种假设。假设：在使用熟悉或新的空间信息的快速新学习过程中形成的HPC表征在内容和潜在的神经生物学机制上会有所不同。熟悉信息的新学习将导致不依赖于NMDAR的速率重映射过程，而新信息的新学习将导致全局重映射。频率重映射可以由电压门控钙通道（VGCC）介导的非NMDA形式的LTP支持，而全局重映射需要两种形式的可塑性。我们将使用电生理学，成像，行为药理学和免疫组织化学技术来评估HPC表示将如何不同时，学习使用熟悉与新的空间信息。 影响：人们已经做出了重大努力，旨在解释暴露于特定事件如何塑造行为，负责的神经网络以及支持这些功能的生化机制。理解HPC如何代表个人在复杂世界中导航所使用的不同体验以及支持这些功能的潜在神经生物学机制对于理解正常和异常行为表现的基础至关重要。这项工作将进一步加深我们对精神疾病的性质和原因的理解，包括成瘾，焦虑，创伤后应激障碍和肥胖。我们试图提供有关何时需要HPC NMDAR介导的LTP用于哺乳动物学习的关键信息，因为在这一领域仍有很大的发现，创新和影响空间。