The brain plays a pivotal role in integrating homeostatic signals and regulating whole-body metabolism. But the high energy demand of neurons also makes the CNS highly sensitive to systemic metabolic stress. We are interested in how the brain adapts to both acute and chronic metabolic changes and how such adaptation, in turn, affects the control of organismal physiology by the CNS, at the biochemical, cellular, and circuit levels. Our long-term goal is to harness the molecular and circuit mechanisms underlying these adaptations to target metabolic disorders including obesity and type 2 diabetes as well as certain neurodegenerative diseases.
We employ and design novel systems tools optimized for brain-wide structural mapping (whole-brain labeling, tissue clearing (“CLARITY”) and large-volume light-sheet imaging), in vivo multi-region Ca2+ imaging, and activity/connectivity-defined optogenetics. Based in TSRI, we also develop and apply high throughput screens (small molecules, genomic, proteomic, etc.) in conjunction with circuit-based tools to unleash the power of large scale unbiased screens in intact mammalian brains.
Brain-wide circuit interactions for metabolic sensing and modulation
Many studies have illuminated the crucial role of the hypothalamus in homeostatic regulation. Less is known about how hypothalamic circuits are integrated within the broader brain-wide networks. How do higher brain functions modulate the homeostatic circuits and conversely, how do metabolic fluctuations affect the psychiatric states? How do these interactions change under chronic metabolic challenges and disease conditions? We address these questions by integrating systems, large-scale unbiased screens, and animal models of metabolism, to bridge the gap between molecular metabolism and systems neuroscience in order to provide new insights into the neuronal adaptation to metabolic challenges.
Chemical biology in mammalian brains
A large number of current and potential therapeutic agents work at least in part through the brain. However, unlike their mechanisms of action in peripheral tissues (which are generally better characterized), the neuronal mechanisms of many chemicals and biologics remain poorly understood. This was largely due to the heterogeneity of the mammalian brain (in terms of anatomy, connectivity, and molecular diversity). Leveraging the power of whole-brain imaging and working with the colleagues at TSRI, we aim to develop novel platforms specialized for brain-wide, unbiased profiling of drug actions across multiple modalities (molecules-neurons-circuits) to elucidate the mechanism of action of current and future therapeutics, predict side effects, and facilitate the discovery of novel drug targets for metabolic diseases and beyond.