A rodent model of episodic memory

描述(由申请人提供)：长期目标是了解动物如何及时处理和记忆事件，并为理解记忆障碍提供神经解剖学指导的理论框架。本申请的目的是验证大鼠情节记忆的动物模型，并确定潜在的神经基础。中心假设是，在附带编码后回答一个意想不到的问题需要依赖于海马体的情节记忆。初步研究表明，在记忆存储之前，海马区的CA3区域暂时失活，这支持了这一假设。PIs将通过实现三个具体目标来检验中心假设：(1)检验回答意外问题需要情景记忆的假设。将评估情景记忆、反应和空间过程在回答意外问题中的作用。与情景记忆和空间处理相关的区域(海马体的CA3区)以及反应学习(背外侧纹状体)将被停用，以检验回答意外问题需要情景记忆的假设。(2)检验回答意想不到的问题需要长期记忆的假设。人类的情节记忆是长期记忆的一部分。工作假设是，海马体的CA1区与情节记忆的长期方面有关，而CA3区是情节记忆在短时间和长时间延迟后所必需的。CA3和CA1将在不同的保留间隔挑战下被失活，以绘制附带编码的剧集的保留函数。工作假说是，CA3的失活预计会在短间隔和长间隔延迟下损害情景记忆，这与初步数据一致，而CA1需要连接长延迟。(3)检验CA3从属于情景记忆提取的假设。在初步研究中，记忆储存前CA3的失活会损害情节记忆。目前尚不清楚CA3是否从属于情节记忆的存储或提取。CA3在储存后但在提取之前被失活，以检验CA3从属于情景记忆提取的工作假说。该项目的健康相关性：通过提供与脑损伤、健忘症、阿尔茨海默氏症或其他人类记忆病理相关的记忆缺陷的洞察，识别控制情景记忆的机制可能会极大地造福社会。识别支配情节记忆的机制可能会提高我们对附属于情节记忆的神经底物的理解，并促进人类记忆障碍治疗的发展。事实上，记忆功能的缺陷是许多精神障碍的关键特征，而改善记忆能力是精神障碍和阿尔茨海默病治疗的重要目标。最终，对情景记忆系统的功能神经解剖学的更好理解为开发针对记忆障碍的解剖学靶向药物和分子治疗提供了可能性。

DESCRIPTION (provided by applicant): The long-range goal is to understand how animals process and remember events in time and provide a neuroanatomically guided theoretical framework for understanding memory disorders. The objective of the present application is to validate an animal model of episodic memory in rats and identify the underlying neural substrates. The central hypothesis is that answering an unexpected question after incidental encoding requires episodic memory that is dependent upon the hippocampus. Preliminary studies, in which the CA3 region of the hippocampus was temporarily inactivated before memory storage, support this hypothesis. The PIs will test the central hypothesis by accomplishing three specific aims: (1) To test the hypothesis that answering an unexpected question requires episodic memory. The role of episodic memory, response, and spatial processes in answering unexpected questions will be assessed. Regions implicated in both episodic memory and spatial processing (CA3 region of the hippocampus) as well as response learning (dorsolateral striatum) will be inactivated to test the hypothesis that answering an unexpected question requires episodic memory. (2) To test the hypothesis that answering an unexpected question requires long-term memory. Episodic memory in humans is part of long-term memory. The working hypothesis is that the CA1 region of the hippocampus is implicated in long-term aspects of episodic memory whereas CA3 is required for episodic memory after both short and long delays. CA3 and CA1 will be inactivated under varying retention-interval challenges to map out the retention function for incidentally encoded episodes. The working hypothesis is that CA3 inactivation is expected to impair episodic memory under short- and long-interval delays, consistent with preliminary data, whereas CA1 is required to bridge long delays. (3) To test the hypothesis that CA3 subserves retrieval of episodic memories. In preliminary studies, inactivation of CA3 before memory storage impaired episodic memory. It is not known if CA3 subserves storage or retrieval of episodic memories. CA3 will be inactivated after storage but before retrieval to test the working hypothesis that CA3 subserves episodic memory retrieval. Health relatedness of the project: Identifying mechanisms that govern episodic memory may significantly benefit society by providing insights into deficits in memory associated with brain injuries, amnesia, Alzheimer's disease or other human memory pathologies. Identifying mechanisms that govern episodic memory may improve our understanding of the neural substrates subserving episodic memory and foster development of treatments for human memory disorders. Indeed, deficits in memory function are key features of many psychiatric disorders and improving memory ability is an important objective for therapies of psychiatric disorders and Alzheimer's disease. Ultimately, a better understanding of the functional neuroanatomy of episodic memory systems offer the potential to develop anatomically targeted pharmacological and molecular treatments for memory disorders.