Hippocampal-prefrontal interactions underlying learning and memory

描述（由申请人提供）：研究形成记忆和使用过去的经验来指导行为的能力是神经系统最显着的能力之一。多个脑区相互作用以支持学习和决策的复杂认知过程，而海马和内侧前额叶皮层（PFC）在这些过程中起着重要作用。海马体是快速情景学习和记忆所必需的，而前额叶皮层对记忆巩固和提取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PFC中的神经活动与许多精神障碍有关，包括PTSD、抑郁症、焦虑症和精神分裂症。我的长期目标是了解行为过程中大脑前额叶与大脑前额叶相互作用的生理基础，以及在病理状态下这些过程的功能障碍。这个建议的目的是调查的性质和作用，介导的特定的神经活动模式，清醒的尖波波纹（SWR），在学习和记忆引导的决策的前额叶皮层-PFC的相互作用。首先，我将在清醒行为动物的学习过程中使用海马和PFC中的多点多电极记录来验证在清醒SWRs期间海马中的记忆重放激活PFC中的记忆模式的假设。其次，我将利用一种用于实时检测和破坏清醒SWRs的新技术来调查清醒SWRs是否需要PFC中稳定的记忆模式的形成。我将通过使用PFC活性的光遗传学抑制来确定在清醒的SWRs在记忆引导的决策过程中，大脑皮层-PFC相互作用的因果作用，这种抑制取决于行为过程中清醒的SWRs的实时检测。这些实验将促进我们对海马和PFC之间记忆活动传播的理解，并提供将生理现象与行为联系起来的直接和因果证据。我广泛的兴趣是理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者，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，并了解这些过程中的功能障碍如何导致疾病的病理状态。我想综合运用多种技术，包括对行为动物的电生理记录、生理模式的实时检测和操纵，以及行为过程中特定回路中神经活动的扰动，来确定生理现象和行为之间的因果关系。在此应用程序的培训阶段，我将获得概念，技术和职业发展方面的额外技能，这将使我能够成功过渡到我自己的研究小组的独立职位。我的短期目标是，1）提高我对前额叶皮层（PFC）生理学的认识，并获得海马和PFC多位点记录的专业知识，2）进一步熟练掌握数据分析技能，3）获得清醒行为啮齿动物同时光遗传学操作和生理学的专业知识，4）提高我在临床研究方面的知识，5）获得一个独立的终身助理教授职位，并在2年内转移到本提案的R 00部分，以及6）在本提案的5年内成功获得R 01资金。环境“UCSF充满活力的合作研究环境有利于实现这些目标。我的共同导师和顾问在前额叶生理学和光遗传学以及海马和前额叶疾病的病理生理学方面拥有丰富的经验。通过我的共同导师和顾问，我还可以访问UCSF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。“UCSF还提供学术课程，我将利用这些课程来获得这些 研究技能。UCSF提供了一些职业发展资源，以帮助博士后获得实现独立所需的额外技能，其中包括研讨会和课程，旨在为博士后准备学术就业市场和专门的资源，帮助博士后申请学术工作。我将利用所有这些资源来提高我的职业技能。“我将在会议上和定期在部门研讨会上介绍我的科学工作。我还将参加加州大学旧金山分校提供的赠款写作，实验室管理和教学研讨会。

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.