Neurobiological Mechanisms subserving Episodic and Incremetal Learning

描述（由申请人提供）：本提案旨在研究支持不同形式长期记忆的神经生物学机制，并探索它们之间的关系。情景记忆是指对新事件的有意识记忆，依赖于内侧颞叶（MTL）。渐进式刺激-反应学习是指通过多次试验逐渐学习刺激-反应规律，被认为依赖于基底神经节（BG）。虽然最初的证据表明，这些形式的记忆的神经基质作为不同的和独立的记忆系统运作，但最近的数据交替表明，MTL和BG可能共同促进两种形式的知识，或者这些神经系统之间可能存在竞争性的相互作用。除了MTL和BG，其他数据表明，这两种形式的记忆的获取和表达都是由前额叶皮层（PFC）调节的。本研究将探讨MTL、BG和PFC对情景学习和增量学习的贡献，以及它们之间的关系。我们将使用功能磁共振成像（fMRI）来检查学习过程中每个系统内部和之间活动的时间动态。我们特别致力于了解学习过程中神经活动的时间分布如何与记忆表现的变化相关（专家1-3）。随后，我们将通过确定每个系统的调制如何影响另一个系统的活动和性能，更直接地检查系统之间关系的本质。这些fMRI研究将测试这些系统之间是否存在功能耦合或竞争，这种相互作用如何随时间变化，以及系统之间的相互作用是直接的还是介导的（专家4-6）。最后，我们将结合脑电图（EEG）和经颅磁刺激（TMS），具体研究PFC在渐进式和情景式学习中的作用，以及在学习过程中调解系统间相互作用的作用。脑电图将明确PFC对情景学习和增量学习的贡献（见图7-8），获得的fMRI和脑电图数据将指导经颅磁刺激对PFC功能的破坏，以测试PFC机制对学习的必要性（见图9-10）。总的来说，拟议的研究将促进对MTL、BG和PFC参与情景学习和增量学习的时空特征的理解，包括这些神经系统之间的相互作用是否以及如何影响记忆。由此产生的知识将为理解与MTL、BG和PFC功能障碍（包括精神分裂症）相关的各种神经系统疾病和精神障碍中的记忆障碍提供基础。事实上，虽然不是这个提议的一部分，我们将直接利用这些研究的结果来为我们对精神分裂症的记忆缺陷的调查提供信息（与Carol Tamminga博士合作）。

DESCRIPTION (provided by applicant): This proposal aims to examine the neurobiological mechanisms that subserve distinct forms of long-term memory, and to explore the relationship between them. Episodic memory refers to conscious memory for new events, and depends on the medial temporal lobe (MTL). Incremental stimulus-response learning refers to gradual learning of stimulus-response regularities over many trials, and is thought to depend on the basal ganglia (BG). While initial evidence has suggested that the neural substrates of these forms of memory operate as distinct and independent memory systems, recent data alternately suggest that the MTL and BG may jointly contribute to both forms of knowledge or that there may be a competitive interaction between these neural systems. Beyond MTL and BG, other data indicate that the acquisition and expression of both of these forms of memory are modulated by prefrontal cortex (PFC). The proposed research will address fundamental questions regarding the nature of MTL, BG, and PFC contributions to episodic and incremental learning, and the relationship between them. We will use fMRI to examine the temporal dynamics of activity within, and between, each system over the course of learning. We specifically aim to understand how the temporal profile of neural activity during learning relates to changes in memory performance (Expts 1-3). We will subsequently examine the nature of the relationship between the systems more directly, by determining how modulation of each system impacts activity and performance of the other. These fMRI studies will test whether functional coupling or competition exists between these systems, how such interactions change over time, and whether putative between-system interactions are direct or mediated (Expts 4-6). Finally, we will specifically examine the role of PFC in incremental and episodic learning, and in mediating putative between-system interactions during learning, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS). EEG will specify the temporal profile of PFC contributions to episodic and incremental learning (Expts 7-8), and the obtained fMRI and EEG data will guide TMS disruption of PFC function to test the necessity of PFC mechanisms for learning (Expts 9-10). Collectively, the proposed research will advance understanding of the temporal and spatial characteristics of MTL, BG, and PFC involvement in episodic and incremental learning, including whether and how interactions between these neural systems impact memory. The resulting knowledge will provide a foundation for understanding memory impairments in various neurological diseases and mental disorders that are associated with MTL, BG, and PFC dysfunction, including schizophrenia. Indeed, while not part of this proposal, we will draw directly on the outcomes from these studies to inform our investigations of memory deficits in schizophrenia (in collaboration with Dr. Carol Tamminga).