Learning, Prefrontal Cortex, and Multiple Memory Systems

描述(申请人提供)：学习，前额叶皮质，和多重记忆系统学习，要有用，必须对情境的相关特征敏感，有指导 环境机会，以及过去类似情况下的行动所提供的信息。换句话说，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是至关重要的，新纹状体对于习惯学习是重要的，需要前额叶皮质(PFC)来灵活地修改先前学习的反应。这些大脑区域中每一个的功能障碍或它们的连接中断都会导致神经精神障碍，包括痴呆症、创伤后应激障碍和精神分裂症。这项提案将调查这些结构在记忆引导学习过程中是如何相互作用的。这些实验是关于前额叶皮质如何促进记忆和认知的更大研究计划的一部分，将检验这样一种假设，即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、事件序列和刺激定向动作为记忆引导学习提供关键机制。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。目标1将通过暂时中断局部电路来评估学习过程中PFC、海马体和DLS之间的功能相互作用。老鼠将被训练成两种行为 同样的迷宫任务，一个需要海马体，另一个需要DLS来进行初始学习~PFC需要在它们之间切换。PFC和其他结构之间的相互作用将暂时通过mPFC和其他结构中的一个进行测试，这些结构都位于大脑的另一边。如果灵活学习需要PFC交互作用，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障碍。目标2将同时记录这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。我们最近在海马体中发现了预测记忆恢复的脑电模式，并发现DBS既可以模仿这些模式，也可以在其他方面健忘的动物中恢复记忆。因此，目标3将通过结合单侧失活、双侧记录和DBS来测试PFC和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，或者反之亦然，这将决定每个结构中的正常编码依赖于另一个结构的程度，以及这些相互作用如何影响学习。有针对性的DBS模式将被用来模拟电路内和电路之间的识别信号，以确定是否可以克服失活的影响，或者是否可以修改学习策略。这一结果将通过揭示PFC、海马体和DLS如何相互作用来实现记忆引导学习，从而推动神经科学的发展，并将为神经精神障碍的新兴治疗提供信息，这些疾病涉及前额叶皮质、海马体和纹状体功能的瓦解，包括精神分裂症和阿尔茨海默病。

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.