Project Summary/Abstract With the long-term research goal of advancing anesthesia through developing new tools and techniques for better anesthetic management and pain control, the candidate focuses his research on elucidating the mechanisms underlying anesthesia, in particular, the role of hypothalamic orexin (Ox) circuit in anesthesia and analgesia. How anesthetics interact with brain neural network is still poorly understood. The Ox circuit is considered to be a master regulator in sleep/wakefulness. The candidate's recent work showed that activation of Ox neurons with chemogenetic approach facilitates emergence from isoflurane anesthesia and induces analgesia. Building upon these findings, he proposes to apply optogenetics to specifically activate subsets of Ox projections to address the underlying mechanisms. The candidate started with mapping the basic neuroanatomy of the Ox projections in the mouse brain. In his preliminary work, he mapped out three-dimensional Ox projections using both confocal and lightsheet microscopy and identified three interesting regions he will focus on in this proposal. In aim 1, he will test the hypothesis that Ox neurons regulate arousal state during anesthesia via their projections to basal forebrain (BF) and lateral habenula (LHb). In aim 2, he plans to test the hypothesis that Ox projections to periaqueductal gray (PAG) contributes to analgesia. While manipulating neuronal activities with optogenetic tools, the candidate will record electroencephalogram (EEG), image in vivo neural calcium activities, and test the animal's behavior related to arousal state or pain. The proposed work will lead to the identification of novel roles of different subsets of Ox projections in anesthesia-related arousal and pain control. The candidate is currently an Assistant Professor in the Department of Anesthesia and Perioperative Care at the University of California San Francisco (UCSF). His career goal is to become an independent physician scientist dedicated to understanding the mechanisms governing anesthesia and bring patient care to the next level with safer and more efficient anesthesia. The candidate has outstanding institutional support with 75% protected research time, lab and office space, administrative support, and department funding for a technician and selected equipment. UCSF is a world-class institute and the candidate has a multidisciplinary mentoring team to guide his career development. Additionally, he has an extensive didactic plan to take advanced training in the next few years to further build a solid foundation for his expertise in the research on the role of neural circuits in anesthesia and analgesia.