Physiological Mechanisms of Hippocampal-Striatal Interactions

描述（由申请人提供）：尽管越来越多的证据表明，不同类型的记忆在特定情况下（正常和病理）的相互作用不同，但可能支持这些过程的神经生理学相关性仍然未知。包括空间表征在内的陈述性记忆依赖于以海马体（HPC）为中心的神经网络，而包括刺激-反应关联在内的习惯则需要完整的背纹状体（DS）。最近，研究表明，内侧DS （DSM）具有空间导航功能，而外侧DS （DSL）负责线索-运动反应关联。空间学习和运动学习可以同时发生，并对行为输出产生共同影响，同时也直接相互影响。我们的长期目标是表征HPC-DS相互作用的神经生理基础。当前提案的目的是通过测试DSM活动是否直接影响记忆依赖的HPC活动模式（如编码旅程起点和目的地的海马旅程依赖活动（HJDA））来评估DSM对HPC活动的潜在贡献。我们的中心假设是，HJDA是通过处理局部海马体网络中的信息并编码经验的地方方面而产生的，它与参与目标定向运动输出的AC相结合，以充分指导显性行为。这项研究的基本原理是，一旦我们确定了两种记忆结构中神经活动之间的关系，我们就可以理解HPC和DS神经回路是如何结合起来支持正常和病理行为的。这一假设将通过追求两个具体目标来检验：通过双侧注射DMS暂时失活后大鼠的空间导航或线索反应能力，确定DSM在正迷宫任务中空间导航中的作用；2. 通过记录失活DSM的大鼠在海马注入zeta抑制肽（ZIP；一种与记忆和长期可塑性过程有关的蛋白激酶Mζ抑制剂）后重新获得空间信息的CA1神经活动，确定DSM活性对HJDA的贡献。本研究的预期贡献是确定DSM对空间学习过程中HPC活动的贡献。这一贡献意义重大，因为它将揭示具有不同记忆功能的两种结构的活动如何结合起来指导行为表现。本申请中提出的研究是创新的，因为它通过在已建立的神经基质的行为范式中记录HPC-DSM相互作用的神经基质，同时通过干扰与记忆相关的突触可塑性选择性地破坏与记忆相关的神经放电。

DESCRIPTION (provided by applicant): Despite the accumulating evidence demonstrating that distinct types of memory interact differently in specific circumstances, both normal and pathological, the neurophysiological correlates that may support these processes remain unknown. Declarative memories, which include spatial representations, are dependent on a neural network centered on the hippocampus (HPC), while habits, which include stimulus-response associations, require an intact dorsal striatum (DS). More recently, it has been shown that the medial DS (DSM) has a spatial navigation function, while the lateral DS (DSL) is responsible for cue-motor response associations. Spatial and motor learning can occur simultaneously and can exert concomitant influence on behavioral output, while also directly influencing each other. Our long-term goal is to characterize the neurophysiological substrates of HPC-DS interaction. The objective of the current proposal is to evaluate the potential contribution of DSM to HPC activity by testing whether DSM activity directly influences memory- dependent HPC activity patterns such as hippocampal journey-dependent activity (HJDA) which encodes origin and destination of journeys. Our central hypothesis is that HJDA, generated through processing of information in the local hippocampal network and encoding the where aspects of experience, combines with AC, involved in goal-directed motor output, to adequately guide overt behavior. The rationale underlying the proposed research is that once we identify the relationship between neural activities in the two memory structures, we can understand how HPC and DS neural circuits may combine to support normal and pathological behavior. The hypothesis will be tested by pursuing two specific aims: 1. Identify the role of DSM in spatial navigation in the plus maze task by assessing rats' ability to engage in spatial navigation or cue response a plus maze after temporary inactivation of DMS through bilateral muscimol infusions in the area; 2. Identify the contribution of DSM activity to HJDA by recording CA1 neural activity in rats with inactivated DSM that reacquire spatial information after hippocampal infusion of zeta inhibitory peptide (ZIP; an inhibitor of protein kinase Mζ that has been linked to memory and long-term plasticity processes). The expected contribution of the proposed research is to identify the contribution of DSM to HPC activity during spatial learning. This contribution is significant because it will reveal how the activity in two structures with distinct memory functions may combine to guide behavioral performance. The research proposed in this application is innovative because it investigates the neural substrate of HPC-DSM interaction by recording in a behavioral paradigm with established neural substrate while selectively disrupting memory-related neural firing through interference with memory-related synaptic plasticity.