Modulating somatosensory network to target metabolic diseases

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Abstract Monitoring the metabolic states of internal organs is crucial for maintaining homeostasis and is believed to be primarily mediated by the vague nerve within the autonomic nervous system. The somatosensory nervous system, characterized by clusters of first-order neurons which reside in the dorsal root ganglia (DRG), it is best known for its role in thermosensation, touch perception, pain, and proprioception through the skin and musculature. Emerging evidence suggests DRG neurons also heavily project to internal organs, but their structures and physiological functions remain much less understood due to the lack of tools with adequate specificity and efficacy to target peripheral sensory nerves. With our unique background in both neurotechnology and metabolism, we propose a systemic and focused effort to develop transformative technologies specifically designed for the mammalian peripheral nervous system to enable optical imaging of whole-body sensory network, innervating target-defined molecular profiling, and organ-specific sensory neuromodulation. The goal of this proposal is to leverage these technologies to unravel the structural, molecular and functional basis of the somatosensory circuitry innervating metabolic organs, with which we will test the central hypothesis that internal somatosensory network is critical for maintaining whole-body metabolic homeostasis by sensing organ-specific metabolic states, and this specificity is determined by the unique topological and molecular characteristics of organ-targeting DRG neurons. A striking finding of our preliminary study was the discovery of a morphologically dense, molecularly distinct, yet historically under-appreciated sensory network innervating adipose tissues. We will first test if fat- specific signals are being conveyed by the DRG neurons upon metabolic challenges and whether this transmission is important for maintaining whole-body homeostasis. Ultimately, the knowledge and expertise gained from this initial fat-focused endeavor will serve as a roadmap to expand our interrogation of sensory circuitry to all metabolic organs and will bring potentially revolutionary strategies to treat metabolic disorders. This proposal is an ambitious, potentially transformative, innovative program ideally suited for the New Innovator Award as it breaks traditional field barriers to establish a new frontier of neurobiology: First, the full revelation of the internal somatosensory network could be paradigm-shifting by challenging the conventional division between exteroception and interoception. Second, a major goal of this proposal is to develop the long- awaited circuit tools designed for the peripheral nervous system, which would potentially have a broader impact on the field by providing a universal, adaptive, and powerful strategy to study the peripheral nervous system. Finally, this project uniquely leverages my interdisciplinary expertise in neurotechnology, molecular biology, and metabolism to spearhead the exploration of a new exciting area of neurobiology and physiology.