Discoveries made in sensory biology not only shape the way we live, but also have important repercussions for human health. My long-term career goal is to better understand how environmental cues are detected and encoded in the periphery, and communicated with the brain to control physiology and behavior in health and disease. My current objective described in this proposal is to investigate how GLP-1 communicates centrally with the subfornical organ to control water intake and body fluid homeostasis. Maintaining fluid homeostasis is crucial for health and disease. Elevation of circulatory osmolarity by high glucose causes polydipsia in diabetic patients. Incretin therapies that involve mimicry or stabilization of glucagon-like peptide 1 (GLP-1) provide a strategy for treatment of type 2 diabetes. As an incretin, GLP-1 not only controls insulin release and feeding behavior but also regulates blood pressure, renal excretion of sodium, and fluid intake to coordinately promote digestion at a systematic level after meal. Intriguingly, acute GLP-1 administration elicits hypodipsia and effectively reduces water consumption in both healthy subjects and diabetic patients, suggesting an alternative strategy for alleviating polydipsia in diabetic patients. Among the many sites that express the receptor for GLP- 1 (GLP1R), the subfornical organ is a major brain center that controls water intake and fluid homeostasis. My central hypothesis is that SFO GLP1R neurons integrate satiety signals after meal to control fluid intake through specific signaling cascades and central neural circuits. I will test this hypothesis through three specific aims: to determine the effect of SFO GLP1R neuron stimulation on fluid intake (Specific Aim 1), to decipher GLP1R signaling pathways in these cells (Specific Aim 2), and to scrutinize their anatomical and functional connectivity (Specific Aim 3). For the training necessary for Specific Aim 2, I will continue to greatly benefit from the guidance of my mentor Prof. Liberles, who has incredible knowledge and understanding in GPCR signaling pathways. To carry out Specific Aim 1 and 3, I will also need to broaden my knowledge and skills to include mouse behavior and neurocircuit mapping, such as stereotaxic brain surgeries, brain slice electrophysiology, and chemogenetics. Such knowledge and skills will be obtained from training with my co- mentor, Prof. Bradford Lowell. I have received tremendous guidance from Prof. Lowell and his lab members in the past, with generation of Glp1r-ires-Cre mice and brain stereotaxic injection. I will continue to learn brain slice recording, rabies virus-based tracing, channelrhodopsin-assisted circuit mapping (CRACM), and DREADD-involved behavioral experiments under the guidance of Prof. Lowell. Particularly regarding the anatomical tracing of SFO GLP1R neurons (Specific Aim 3) that requires very extensive knowledge of brain anatomy, I will collaborate with Prof. Clifford Saper, who is an expert in neuroanatomy more than 40 years experience. Together, these studies will greatly expand our knowledge on how GLP-1 signal is integrated in the brain to coordinately control physiology and shed light on GLP-1 based drug design.
This proposed research will help uncover the neural basis for the integration of satiety and thirst cues by a single hormone GLP-1 that is released after meal. Understanding the cellular mechanism by which the GLP-1 system regulates body fluid homeostasis will 1) provide insights for alleviating polydipsia in diabetic patients and 2) shed light on design of GLP-1 based therapies with improved specificity and efficacy.