Hippocampal-prefrontal interactions underlying learning and memory

项目摘要/摘要 研究 形成记忆并利用过去的经验来指导行为的能力是最显著的能力之一 神经系统的能力。多个大脑区域相互作用以支持复合体 学习和决策的认知过程，以及海马体和内侧前额叶皮质(PFC) 在这些过程中发挥重要作用。海马体对于快速间歇性学习和 记忆，而PFC对记忆巩固和提取以及决策等认知功能至关重要。 制造和工作记忆。这些结构如何相互作用以支持行为仍然很差 明白了。此外，海马区和前额叶的神经活动与许多精神疾病有关 精神障碍，包括创伤后应激障碍、抑郁、焦虑和精神分裂症。我的长期目标是理解 行为过程中海马体-前额叶相互作用的生理学基础及其功能障碍 处于病态。本研究的目的是探讨海马-PFC的性质和作用。 学习中由一种特殊的神经活动模式--觉醒的尖锐波纹(SWR)--介导的相互作用 以及记忆引导的决策。首先，我将在海马体中使用多点多电极记录 和PFC在清醒的动物学习期间的行为来测试记忆在大脑中重放的假说 清醒时的海马区SWR激活PFC中的助记模式。第二，我将利用一个 实时检测和中断唤醒SWR以调查唤醒SWR是否 在PFC中形成稳定的记忆模式所需的。最后，我将确定 利用光发生技术实现记忆引导决策中清醒SWR时的海马神经元-PFC相互作用 抑制PFC活动取决于在行为过程中实时检测唤醒的SWR。这些实验 将促进我们对记忆活动在海马体和PFC之间的传播的理解，以及 提供将生理现象与行为联系起来的直接和因果证据。 侯选人 我的广泛兴趣在于了解行为的神经生理学基础。我的长期目标是 成为一名独立的研究员，拥有一个实验室，专注于研究不同的大脑结构如何 相互作用以支持复杂的认知过程，如学习和决策，以及 了解这些过程中的功能障碍如何导致疾病的病理状态。我想用一个 技术组合，包括动物行为的电生理记录，实时检测 和生理模式的操纵，以及在特定回路中神经活动的扰动 行为，以确定生理现象和行为之间的因果联系。在培训阶段 在这份申请中，我将在概念、技术和职业发展方面获得额外的技能 将使我能够成功地过渡到我自己的研究小组的独立职位。我的 短期目标是：1)提高我对前额叶皮质(PFC)的生理学知识，并获得 在海马体和PFC的多点记录方面的专业知识，2)进一步熟练掌握数据 分析技能，3)在清醒状态下同时获得光遗传操作和生理学方面的专业知识- 表现为啮齿动物，4)提高我在临床方面的研究知识，5)获得 独立终身教职-跟踪助理教授职位，并在2年内转到本提案的R00部分 6)在本提案提出后5年内成功获得R01资金。 环境 ·加州大学旧金山分校充满活力和协作的研究环境有助于实现这些目标。我的 合作导师和顾问在前额叶生理学和光遗传学方面拥有丰富的经验，而且 在海马区和前额叶疾病的病理生理学方面。通过我的共同导师和顾问， 我还可以访问加州大学旧金山分校的欧内斯特·加洛诊所和研究中心，这将有助于这些研究 目标。 ·加州大学旧金山分校还提供学术课程，我将利用这些课程获得这些研究技能。加州大学旧金山分校提供一个数字 职业发展资源，以帮助博士后研究员获得所需的额外技能 独立性，包括旨在为学术工作准备博士后的研讨会和课程 市场和专门的资源，帮助博士后申请学术工作。我会利用所有这些 增强我的职业技能的资源。 ·我将在会议上介绍我的科学工作，并定期在部门研讨会上介绍我的工作。我也会参加 加州大学旧金山分校提供写作、实验室管理和教学研讨会。

Project Summary / Abstract Research The ability to form memories and use past experience to guide behavior is one of the most remarkable capacities of the nervous system. Multiple brain regions interact with each other to support the complex cognitive processes of learning and decision-making, and the hippocampus and medial prefrontal cortex (PFC) play important roles in these processes. The hippocampus is necessary for rapid episodic learning and memory, while PFC is crucial for memory consolidation and retrieval, and for cognitive functions like decision- making and working memory. How these structures interact with each other to support behavior is still poorly understood. Further, neural activity in the hippocampus and PFC is implicated in numerous psychiatric disorders, including PTSD, depression, anxiety and schizophrenia. My long-term goal is to understand the physiological bases of hippocampal-prefrontal interactions during behavior, and dysfunction in these processes in pathological states. The objective of this proposal is to investigate the nature and role of hippocampal-PFC interactions mediated by a particular neural pattern of activity, awake sharp wave ripples (SWRs), in learning and memory-guided decision making. First, I will use multisite multielectrode recordings in the hippocampus and PFC in awake behaving animals during learning to test the hypothesis that memory replay in the hippocampus during awake SWRs activates mnemonic patterns in PFC. Second, I will take advantage of a novel technique for real-time detection and disruption of awake SWRs to investigate if awake SWRs are required for formation of stable memory patterns in PFC. Finally, I will determine the causal role of hippocampal-PFC interactions during awake SWRs in memory-guided decision making by using optogenetic inhibition of PFC activity contingent on real-time detection of awake SWRs during behavior. These experiments will advance our understanding of propagation of mnemonic activity between the hippocampus and PFC and provide direct and causal evidence linking physiological phenomena to behavior. Candidate My broad interests are in understanding the neurophysiological basis of behavior. My long-term goal is to become an independent investigator with a lab that focuses on investigating how different brain structures interact with each other to support complex cognitive processes such as learning and decision-making, and understanding how dysfunction in these processes leads to pathological states in disease. I want to use a combination of techniques, including electrophysiological recordings in behaving animals, real-time detection and manipulation of physiological patterns, and perturbation of neural activity in specific circuits during behavior, to determine causal links between physiological phenomena and behavior. During the training phase of this application, I will gain additional skills in conceptual, technical and career development aspects which will enable me to make a successful transition to an independent position with my own research group. My short-term goals are, 1) to improve my knowledge about pre-frontal cortex (PFC) physiology and to gain expertise in multi-site recordings in the hippocampus and PFC, 2) to acquire further proficiency in data analyses skills, 3) to gain expertise in simultaneous optogenetic manipulations and physiology in awake- behaving rodents, 4) to improve my knowledge in the clinical aspects of my research, 5) to obtain an independent tenure-track assistant professor position and transfer to the R00 portion of this proposal within 2 years, and 6) to successfully obtain R01 funding within 5 years of this proposal. Environment • The vibrant, collaborative research environment at UCSF is conducive to the attainment of these goals. My co-mentors and consultants have extensive experience in prefrontal physiology and optogenetics, and also in the pathophysiology of hippocampal and prefrontal disorders. Through my co-mentorship and consultants, I also have access to UCSF's Ernest Gallo Clinic and Research Center, which will aid in these research goals. • UCSF also offers academic courses that I will utilize to gain these research skills. UCSF provides a number of career development resources to help postdoctoral fellows gain additional skills required to achieve independence, which include seminars and classes aimed at preparing postdocs for the academic job market and a dedicated resource that helps postdocs apply for academic jobs. I will utilize all these resources to enhance my career skills. • I will present my scientific work in conferences and regularly in departmental seminars. I will also attend grant writing, lab management and teaching workshops offered at UCSF.