Learning, Prefrontal Cortex, and Multiple Memory Systems

描述（由申请人提供）：学习，前额叶皮层和多记忆系统 学习要有用，必须对情境的相关特征敏感， 环境机会，并通过过去在类似情况下的行动来了解。换言之，学习是由记忆引导的。整合学习和记忆的神经机制在很大程度上是未知的。海马体对于学习事实和记忆事件至关重要，新纹状体对于习惯学习至关重要，而前额叶皮层（PFC）则需要灵活地修改先前学习的反应。 这些大脑区域中的每一个的功能障碍或它们的断开有助于神经精神疾病，包括痴呆症、创伤后应激障碍和精神分裂症。这个建议将调查这些结构如何在记忆引导的学习过程中相互作用。这些实验是关于前额叶皮层如何促进记忆和认知的更大研究计划的一部分，将测试PFC，海马和背外侧纹状体（DLS）回路之间的相互作用通过整合抽象规则，事件序列和刺激导向的行为为记忆引导学习提供关键机制的假设。具体目标将通过结合行为分析、暂时失活、同时记录神经元活动和脑深部刺激来研究这些机制。 目的1将评估在学习过程中，通过局部回路的暂时中断，PFC，海马和DLS之间的功能相互作用。大鼠将被训练到两个行为 相同的+迷宫任务，一个需要海马体，另一个需要DLS进行初始学习-PFC需要在它们之间切换。PFC和其他结构之间的相互作用将通过暂时的mPFC和其他结构之一来测试，这两个结构都位于大脑的相对侧。如果前额叶皮层的相互作用是灵活学习所必需的，那么“交叉失活”应该会在从一种策略切换到另一种策略时产生不对称的损伤。目标2将同时记录三个结构中的神经元活动，以确定PFC和其他结构内部和之间的活动如何预测学习。我们最近发现海马体中的EEG模式可以预测记忆提取，并发现DBS可以模仿这些模式并恢复其他健忘动物的记忆。因此，目标3将通过结合单侧失活、双侧记录和DBS来测试PFC与其他结构之间的因果关系。 在PFC中进行记录，同时单方面扰乱海马体或DLS的活动，反之亦然，将确定每个结构中的正常编码对另一个结构的依赖程度，以及这些相互作用如何影响学习。DBS的目标模式将用于模拟回路内和回路之间的识别信号，以确定是否可以克服失活的影响或修改学习策略。该结果将通过揭示PFC，海马和DLS如何相互作用以允许记忆引导学习来推进神经科学，并将为涉及前额叶皮层，海马和纹状体功能解体的神经精神疾病（包括精神分裂症和阿尔茨海默病）的新兴治疗提供信息。

DESCRIPTION (provided by applicant): Learning, Prefrontal Cortex, and Multiple Memory Systems Learning, to be useful, must be sensitive to the relevant features of situations, guided by environmental opportunities, and informed by past actions in similar circumstances. In other words, learning is guided by memory. The neuronal mechanisms that integrate learning and memory are largely unknown. The hippocampus is crucial for learning facts and remembering events, the neostriatum is important for habit learning, and the prefrontal cortex (PFC) is needed to modify previously learned responses flexibly. Dysfunction of each of these brain regions or their disconnection contributes to neuropsychiatric disorders including dementia, PTSD, and schizophrenia. This proposal will investigate how these structures interact during memory-guided learning. The experiments, part of a larger research program on how prefrontal cortex contributes to memory and cognition, will test the hypothesis that interactions between PFC, hippocampal and dorsolateral striatal (DLS) circuits provide key mechanisms for memory guided learning by integrating abstract rules, event sequences, and stimulus-directed actions. The specific aims will investigate these mechanisms by combining behavior analysis, temporary inactivation, simultaneous recording of neuronal activity, and deep brain stimulation. Aim 1 will assess the functional interactions between the PFC, hippocampus, and DLS the during learning by temporary disruption of local circuits. Rats will be trained to two behaviorally identical + maze tasks, one that requires the hippocampus, the other the DLS for initial learning~ the PFC is needed to switch between them. Interactions between the PFC and the other structures will be tested by temporarily the mPFC and one of the other structures both the on opposite side of the brain. If PFC interactions are required for flexible learning, then the "crossed inactivation" should produce asymmetric impairments in switching from one strategy to the other. Aim 2 will record neuronal activity in the three structures simultaneously to determine how activity within and between the PFC and the other structures predict learning. We recently identified EEG patterns in the hippocampus that predicted memory retrieval, and discovered that DBS could both mimic these patterns and restore memory in otherwise amnestic animals. Aim 3 will therefore test the causal relationships between the PFC and the other structures by combining unilateral inactivation, bilateral recordings, and DBS. Recording in PFC while disrupting activity unilaterally in the hippocampus or DLS, or vice versa, will determine the extent to which normal coding in each structure depends on the other, and how these interactions influence learning. Targetted patterns of DBS will be used to mimic identified signals within and between circuits to determine if the effects of inactivation can be overcome, or learning strategy modified. The outcome will advance neuroscience by revealing how the PFC, hippocampus, and DLS interact to allow memory-guided learning, and will inform emerging treatments for neuropsychiatric disorders that involve disintegration of prefrontal cortex, hippocampal, and striatal functions, including schizophrenia and Alzheimer's disease.