PROJECT SUMMARY/ABSTRACT This is an application for the Mentored Clinician Scientist Career Development Award (K08) for Dr. Maggie Waung, a Clinical Instructor in Neurology at the University of California, San Francisco. Dr. Waung is establishing herself as a young investigator in the translational field of headache disorders. This proposal describes a 5-year training program (coursework, conferences, national presentations, clinical development, and mentored research) geared towards the development of an academic career focused on studying the mechanisms of chronic headache, with a particular focus on migraine. This award will provide the core support necessary to acquire further expertise in advanced neuroscience methods and develop the leadership skills required to successfully run an independent laboratory. To achieve these goals, Dr. Waung has outlined a detailed plan and assembled a mentoring team composed of experts in the field of pain, addiction, and complex neural circuits. The Candidate: Dr. Waung is a neurologist and neuroscientist who graduated from the Medical Scientist Training Program at the University of Texas, Southwestern Medical Center, where she excelled in both her medical and graduate school studies. She was elected to the Alpha Omega Alpha (AOA) medical honors society and received the American Academy of Neurology Medical Student Prize for Excellence in Neurology. Her graduate work uncovered a novel mechanism underlying persistent postsynaptic changes in a unique form of hippocampal synaptic plasticity. This led to a first-author publication in a major neuroscience journal, Neuron. She continued on to complete neurology residency training at UCSF, where she served as chief resident. In her proposed training plan, Dr. Waung will apply her understanding of neuronal plasticity and learn new methods of circuit analysis in order to build a solid scientific program towards the study of headache. Mentorship Environment and Formal Instruction: Dr. Waung's proposal draws on the resources and expertise of the Fields lab in conjunction with the mentorship of Drs. Elyssa Margolis and Allan Basbaum. Dr. Howard Fields is a Professor of Neurology and Director of the Wheeler Center for the Neurobiology of Addiction. He has made seminal contributions to the understanding of neuropathic pain and the role of endogenous opioids in these circuits, not to mention his tremendous track record in mentoring successful neuroscientists, many who have gone on to pursue academic careers in research. Dr. Allan Basbaum is Professor and Chair of the Department of Anatomy at UCSF, who has devoted his career to understanding the neurobiological basis of pain. Dr. Waung's advisory committee also includes an expert in midbrain opioid signaling (Elyssa Margolis) and Dr. Frederic (Woody) Hopf, who has pioneered the use of optogenetics in novel addiction paradigms. In addition to a remarkable group of mentors, Dr. Waung will participate in formal workshops around the country to supplement her technical and leadership training. She will also take advantage of formal courses at UCSF designed to provide ethical training in research and to develop the professional skills required for becoming an independent investigator at an academic center. Research: Migraine is highly prevalent in the population and leads to significant morbidity and suffering, particularly among women. Dr. Waung aims to identify the relevant changes in neuronal circuitry driving the persistence and worsening of chronic headache. She has identified a connection between pain and reward centers in the brainstem that may be altered in chronic headache. Using immunohistochemical methods and optogenetic manipulation in an animal model, she will determine whether this circuit is activated during headache and contributes to an aversive state (Aim 1). She will further define this connection using electrophysiological and neuronal tract tracing techniques (Aim 2). Finally, she will employ slice pharmacology to test whether or not this connection is affected by headache-specific medications (Aim 3). These studies will develop a circuit model for understanding the underlying mechanisms of headache. Long-term Career Goals: Dr. Waung is currently a Clinical Instructor in the Neurology Department who is on track to be promoted to tenure track Assistant Professor within 3 years. She plans on becoming primarily a laboratory-based scientist with research devoted to studying the underlying mechanisms of headache. Her long-term research objectives are to discover the key neural circuits leading to chronic headache and to uncover the biological basis for the higher prevalence of migraines in women. This project serves the mission of the NIH and the NINDS and fulfills an underserved translational need in the area of headache.