Sympathetic Neural Circuitry Controlling Whole-body Metabolism (360G-Wellcome-315428_Z_24_Z)

The brain regulates physiology, including body weight, through descending autonomic sympathetic neurons. Therefore, mapping the vast, but poorly defined array of sympathetic neurons is critical to understand the neural control of metabolism, particularly obesity. However, the functional mapping of sympathetic neural networks has been hampered by their size and inaccessible anatomical location. My laboratory is developing a unique combination of strategies to discover the sympathetic neural circuits that selectively burn fat. Our approach is based on developing both an anatomical and molecular atlas. We do this using our novel light sheet imaging of the mouse paravertebral sympathetic ganglia which has single-neuron resolution, our novel single-cell algorithms, machine learning-driven spatial transcriptomics and 3) intersectional mouse models to discover the functional relevance of the newly identified sympathetic neuronal networks and their selective effects on controlling metabolism versus as heart rate. This approach has uncovered inhibitory sympathetic interneurons, which were never seen in the peripheral nervous system. These interneurons primarily populate ganglia that do not innervate the heart, offering fundamentally new insights into sympathetic neuroscience and potential cardioprotective anti-obesity mechanisms that burn fat.