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.

Public Health Relevance

Dysfunction in the hippocampus and prefrontal cortex is associated with numerous psychiatric disorders including PTSD, depression, anxiety, schizophrenia and diseases of memory. This proposal aims to investigate the neurophysiological basis of hippocampal-prefrontal interactions supporting memory processes, and also provides direct and causal evidence linking neural activity patterns to behavior. Understanding the role of these basic physiological phenomena during normal behavior will shed light on how dysfunction in these processes leads to pathological states, and has the potential to contribute to the development of new and more effective treatments for these disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Study Section
Special Emphasis Panel (ZMH1)
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Desmond, Nancy L
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Papale, Andrew E; Zielinski, Mark C; Frank, Loren M et al. (2016) Interplay between Hippocampal Sharp-Wave-Ripple Events and Vicarious Trial and Error Behaviors in Decision Making. Neuron 92:975-982