Hippocampal-prefrontal interactions underlying learning and memory

描述(申请人提供)：研究形成记忆并用过去的经验来指导行为的能力是神经系统最显著的能力之一。大脑的多个区域相互作用，支持复杂的学习和决策认知过程，而海马体和内侧前额叶皮质(PFC)在这些过程中发挥着重要作用。海马体是快速情景学习和记忆所必需的，而PFC对记忆巩固和检索以及决策和工作记忆等认知功能至关重要。这些结构如何相互作用以支持行为仍然知之甚少。此外，海马体和前额叶的神经活动与许多精神疾病有关，包括创伤后应激障碍、抑郁、焦虑和精神分裂症。我的长期目标是了解行为过程中海马体-前额叶相互作用的生理学基础，以及在病理状态下这些过程的功能障碍。本研究的目的是研究在学习和记忆引导的决策过程中，由一种特殊的神经活动模式--觉醒尖波纹波(SWRs)所介导的海马-PFC相互作用的性质和作用。首先，我将使用在学习过程中清醒行为的动物的海马区和PFC中的多点多电极记录来测试在清醒SWR期间在海马区的记忆重放激活PFC中的助记模式的假设。其次，我将利用一种实时检测和干扰清醒SWR的新技术来研究PFC中是否需要清醒SWR来形成稳定的记忆模式。最后，我将通过实时检测行为过程中觉醒的SWR来抑制PFC活动，从而确定清醒SWR期间海马-PFC相互作用在记忆引导决策中的因果作用。这些实验将促进我们对记忆活动在海马体和PFC之间传播的理解，并提供将生理现象与行为联系起来的直接和因果证据。候选人我的广泛兴趣是了解行为的神经生理学基础。我的长期目标是成为一个实验室的独立研究员，该实验室专注于研究不同的大脑结构如何相互作用，以支持学习和决策等复杂的认知过程，并了解这些过程中的功能障碍如何导致疾病的病理状态。我想结合使用多种技术，包括动物行为的电生理记录，生理模式的实时检测和操作，以及行为过程中特定回路中神经活动的扰动，以确定生理现象和行为之间的因果联系。在这份申请的培训阶段，我将在概念、技术和职业发展方面获得更多技能，这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)生理学的知识，并获得在海马体和PFC的多点记录方面的专业知识，2)获得进一步熟练的数据分析技能，3)获得同步光遗传操作和清醒行为啮齿动物生理学的专业知识，4)提高我研究临床方面的知识，5)获得一个独立的终身教职跟踪助理教授职位并在2年内转到本建议的R00部分，以及6)在本建议实施后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以及海马体和前额叶疾病的病理生理学方面拥有丰富的经验。通过我的共同指导和顾问，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，这将有助于实现这些研究目标。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了许多职业发展资源，帮助博士后研究员获得获得独立所需的额外技能，其中包括旨在为学术就业市场准备博士后的研讨会和课程，以及帮助博士后申请学术工作的专门资源。我会利用所有这些资源来提升我的职业技能。他说：“我会在会议和定期的部门研讨会上介绍我的科研成果。我还会参加加州大学旧金山分校提供的拨款撰写、实验室管理和教学工作坊。

DESCRIPTION (provided by applicant): 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.