Compartmentalized molecular signaling in neural circuits controlling appetite

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

The purpose of this project is to develop a mechanistic understanding of how compartmentalized G-protein coupled receptor (GPCR) signaling is used by neural circuits to control appetite and to help discover new therapeutic strategies for the treatment of obesity and diabetes. We hypothesize that GPCRs located on presynaptic terminals of neurons involved in the control of appetite are necessary for the ability of GPCR signaling to influence eating. Neurons send long range projections into target areas where local presence of neuromodulators that act on GPCRs may site-specifically regulate synaptic vesicle release. For example, GLP1 receptor expressing neurons of the paraventricular hypothalamus send axons into the parabrachial nucleus where release of GLP1 may specifically impact these axons either by rapid actions on presynaptic vesicle release or via plasticity that alters these axon terminals over longer timescales. We use ex vivo and in vivo two-photon microscopy to visualize axon terminals in several key brain regions known to be necessary for the control of appetite. By expressing fluorescent biosensors that report on intracellular GPCR signaling in specific neuronal populations that send projections to these brain regions, we can measure the dynamics of GPCR signaling. In ex vivo brain slices or via implant optical lenses in the brains of live mice, we study the actions of presynaptic GPCR signaling during food seeking and following changes in the physiological state of animals. This year, the lab uncovered molecular signaling mechanisms by which GLP1R signaling in key brainstem regions mediate the anti-obesity effects of GLP1R agonists in mice.