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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761414
• 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。指导这一研究计划的理论是，哺乳动物大脑中的记忆功能被组织成不同的神经网络，这些神经网络调节着不同的记忆功能。在这个组织中，正常的思想和行为产生于这些不同系统之间的合作和竞争互动。在本研究中，我们重点研究了以海马体为中心的记忆网络的功能及其相关的可塑性机制。这项工作源于对N-甲基- d -天冬氨酸（NMDAR）介导的长期增强（LTP）在莫里斯水任务（MWT）训练过程中空间信息获取中的作用的争论。开创性的行为药理学研究表明，NMDAR LTP对MWT的获得是必要的，而不是表达。然而，后来的研究表明，当使用预训练时，MWT中的空间学习变得与NMDAR无关。我们开发了一种行为范式，试图理解为什么nmdar介导的可塑性机制涉及某些变体的位置学习而不是其他变体。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个假设。假设：在使用熟悉或新的空间信息进行快速新学习时形成的HPC表征在内容和潜在的神经生物学机制上有所不同。使用熟悉信息的新学习将诱导不依赖于NMDAR的速率重映射过程，而使用新信息的新学习将诱导全局重映射。速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当学习使用熟悉的空间信息和新的空间信息时，HPC表征将如何不同。影响：已经做出了重大努力，旨在解释行为是如何通过暴露于特定事件、负责的神经网络以及支持这些功能的生化机制而形成的。理解HPC如何表现个体在复杂世界中所使用的不同体验，以及支持这些功能的潜在神经生物学机制，是理解正常和异常行为表现基础的基础。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。我们试图提供关于HPC nmdar介导的LTP在哺乳动物学习中何时是必需的关键信息，因为在这一领域仍有很大的发现、创新和影响空间。