Prospective Coding and Memory Retrieval

描述(申请人提供)：记忆的目的是引导适应性行为：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。为了有用，记忆提取必须是选择性的，由情景的显著特征指导，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。海马体和眼眶前额叶皮质(OFC)对适应行为的不同方面至关重要，这两个脑区中的任何一个区域的功能障碍都可能导致神经精神障碍，包括阿尔茨海默病、创伤后应激障碍和精神分裂症。这项建议将调查OFC和海马体如何有助于灵活的、目标导向的、记忆引导的行为。这些实验是关于前额叶皮质如何促进记忆的更大研究计划的一部分，将检验这样一个普遍假设，即OFC和海马区之间的双向相互作用通过整合奖赏历史和情节记忆，为选择性提取与目标相关的表征提供了关键机制。具体目标将结合行为分析、暂时失活、同时记录两个结构中的神经元活动以及脑深部刺激(DBS)来研究这些机制。目标1将评估学习和记忆提取过程中两个结构之间的功能相互作用。大鼠将接受+迷宫任务的训练，该任务要么需要一个结构，要么需要另一个，或者两个都需要，或者两个都不需要。这些结构之间的相互作用将通过暂时干扰大脑两侧的一个或另一个或两者来测试。如果灵活的记忆提取需要OFC-海马体的相互作用，那么“交叉失活”应该会产生类似于双侧失活的损伤。Aim 2将同时记录两个结构中的神经元活动，以确定OFC和海马体内和之间的活动如何预测学习和记忆表现。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，AIM 3将通过结合暂时失活、双重录音和DBS来测试OFC和海马区之间的因果关系。记录一种结构，同时扰乱另一种结构的活动，将决定每种结构中的正常编码依赖于另一种结构的程度，以及这些相互作用如何影响学习和记忆。有针对性的DBS模式将被用来模拟海马和OFC电路内部和之间的识别信号，以确定是否可以克服失活的影响，或提高正常性能。这一结果将通过揭示OFC和海马体如何相互作用来指导灵活和选择性地使用记忆来推动神经科学，并将为行为和神经精神障碍的新兴治疗提供信息，这些障碍涉及前额叶皮质和海马体功能的瓦解，包括精神分裂症和阿尔茨海默病。 公共卫生相关性：对最近经历的记忆在阿尔茨海默病早期就受到损害，并与皮质和海马区神经元的损伤有关。行为和记忆的组织依赖于前额叶皮质。拟议的实验将调查前额叶和海马神经元如何相互作用来促进记忆，这是神经科学、神经学和精神病学的一个基本问题。

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. PUBLIC HEALTH RELEVANCE: Memory for recent experience is impaired early in Alzheimer's disease, and associated with damage to neurons in the cortex and hippocampus. The organization of behavior and memory depend upon the prefrontal cortex. The proposed experiments will investigate how prefrontal and hippocampal neurons interact to contribute to memory, a fundamental issue to neuroscience, neurology, and psychiatry.