Prospective Coding and Memory Retrieval

描述（由申请人提供）：记忆的目的是指导适应性行为：我们回忆过去以告知现在，预测选择的结果，从而指导目标导向的反应。为了发挥作用，记忆提取必须是有选择性的，由情况的显著特征来指导，并灵活地适应不断变化的内部目标、环境机会和潜在的行动。海马体和眶前额叶皮层（OFC）对适应性行为的不同方面至关重要，这两个大脑区域的任何一个功能障碍都可能导致神经精神疾病，包括阿尔茨海默病、创伤后应激障碍和精神分裂症。本研究将探讨OFC和海马体如何促进灵活的、目标导向的、记忆引导的行为。这些实验是一个关于前额叶皮层如何促进记忆的大型研究项目的一部分，将测试一个一般假设，即OFC和海马回路之间的双向互动，通过整合奖励历史和情节记忆，为选择性检索目标相关表征提供了关键机制。具体目标将通过结合行为分析、暂时失活、同时记录两个结构中的神经元活动和深部脑刺激（DBS）来研究这些机制。目的1将评估两个结构在学习和记忆检索过程中的功能相互作用。老鼠将接受迷宫任务的训练，这些任务要么需要一种结构，要么需要另一种结构，要么两者都需要，要么两者都不需要。这两个结构之间的相互作用将通过暂时破坏大脑两侧的一个、另一个或两个来测试。如果ofc -海马相互作用是灵活记忆检索所必需的，那么“交叉失活”应该产生与双侧失活相似的损伤。目的2将同时记录这两个结构的神经元活动，以确定OFC和海马体内部和之间的活动如何预测学习和记忆表现。我们最近确定了海马体中预测记忆恢复的脑电图模式，并发现DBS既可以模仿这些模式，又可以恢复失忆动物的记忆。因此，目的3将通过结合暂时失活、双重记录和DBS来测试OFC和海马之间的因果关系。在记录一种结构的同时破坏另一种结构的活动，将确定每种结构的正常编码在多大程度上依赖于另一种结构，以及这些相互作用如何影响学习和记忆。DBS的目标模式将用于模拟海马和OFC回路内部和之间已识别的信号，以确定失活的影响是否可以克服，或者正常性能是否可以增强。该结果将通过揭示OFC和海马体如何相互作用以指导灵活和选择性地使用记忆来推进神经科学，并将为涉及前额叶皮层和海马体功能解体的行为和神经精神疾病（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): Memory's purpose is to guide adaptive behavior: we recall the past to inform the present, to anticipate the outcome of choices, and thereby guide goal-directed responses. To be useful, memory retrieval must be selective, directed by the salient features of situations, and flexible to adapt to changing internal goals, environmental opportunities, and potential actions. The hippocampus and the orbital prefrontal cortex (OFC) are crucial for different aspects of adaptive behavior, and dysfunction of either of these brain regions can contribute to neuropsychiatric disorders including Alzheimer's disease, PTSD, and schizophrenia. This proposal will investigate how the OFC and the hippocampus contribute to flexible, goal-directed, memory guided behavior. The experiments, part of a larger research program on how prefrontal cortex contributes to memory, will test the general hypothesis that bidirectional interactions between OFC and hippocampal circuits provide key mechanisms for selective retrieval of goal-related representations by integrating reward history and memory for episodes. The specific aims will investigate these mechanisms by combining behavior analysis, temporary inactivation, simultaneous recording of neuronal activity in both structures, and deep brain stimulation (DBS). Aim 1 will assess the functional interactions between the two structures during learning and memory retrieval. Rats will be trained in a + maze task that either requires one structure, the other, both, or neither. Interactions between the structures will be tested by temporarily disrupting one, the other, or both on opposite sides of the brain. If OFC-hippocampal interactions are required for flexible memory retrieval, then the "crossed inactivation" should produce similar impairments as bilateral inactivation. Aim 2 will record neuronal activity in both structures simultaneously to determine how activity within and between the OFC and hippocampus predict learning and memory performance. 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 OFC and hippocampus by combining temporary inactivation, dual recordings, and DBS. Recording one structure while disrupting activity in the other will determine the extent to which normal coding in each structure depends on the other,and how these interactions influence learning and memory. Targetted patterns of DBS will be used to mimic identified signals within and between hippocampal and OFC circuits to determine if the effects of inactivation can be overcome, or normal performance enhanced. The outcome will advance neuroscience by revealing how the OFC and hippocampus interact to guide flexible and selective use of memory, and will inform emerging treatments for behavioral and neuropsychiatric disorders that involve disintegration of prefrontal cortex and hippocampal functions, including schizophrenia and Alzheimer's disease.