Decoding the Wiring of Integrative Neurocircuits in Metabolic Control

ongoing

Systemic metabolism has to be constantly adjusted to the internal variance in nutrient availability. Therefore, the brain integrates multiple signals related to energy balance and coordinates alterations in energy intake with fuel distribution by precisely fine-tuning feeding, hormone release, and autonomic output. Cell-specific investigations have shown that this involves various molecularly distinct neurons that are distributed throughout the nervous system, each encoding different aspects of behavior and physiology. However, it has not been possible to comprehensively assess the circuit organization of these functionally distinct cells due to the enormous neuronal heterogeneity and anatomical complexity of the regions they reside in. Addressing this issue would have fundamental implications for elucidating the information network flow within the brain that ultimately orchestrates metabolic processes across cells, tissues, and organ systems. Thus, the proposed research program will employ a newly developed approach for the unbiased identification of the molecular profiles of connected neurons. This knowledge will then be used for targeting engineered neurobiological tools to newly identified neurocircuits in order to characterize their integrative features and metabolic functions with unprecedented precision. This multidisciplinary combinatorial approach will be employed to (1) unravel hypothalamic neurocircuits that integrate hormonal signals, (2) identify the neurocircuits that relay nutrient signals from the gut, and (3) define convergence of hormonal and vagal inputs in distinct neurocircuits. Collectively, the proposed research program will provide a more holistic insight into the integrative wiring diagram of metabolism-regulatory neurocircuits, which could provide long-elusive insights into how their disruption is linked to metabolic disorders, and may even lay the foundation for developing new druggable targets to better treat specific metabolic disorders.