1528-P: Investigate Functional Dynamics of Neuropeptides in Acute Brain Slices to Predict Anorexigenic Efficacy

Obesity represents the largest and rapidly escalating global health crisis in the world, predominantly attributed to a disequilibrium between caloric intake and energy expenditure. Contemporary therapeutic strategies predominantly employ anorexigenic peptides such as GLP-1 and GIP receptor agonists. The physiological response is mediated by specific neuronal clusters of the hypothalamus, particularly the arcuate nucleus, which harbors a complex neuronal network that plays a pivotal role in modulating satiety and hunger signaling within the brain. Therefore, elucidating the neuronal responses within the arcuate nucleus is critical for profiling novel compounds and combinations thereof, to discover innovative and more efficacious therapeutic strategies. We have established an integrated opto-neurophysiology setup that combines functional calcium imaging and electrophysiological recordings in acute brain slices of the hypothalamus. We make use of different cell labeling strategies including chemical and genetically encoded calcium indicators (GECIs) to mark neuronal populations within the arcuate nucleus, and have successfully captured distinct neuronal responses to various neuropeptides within a suitable assay window. Our platform enables sequential monitoring of individual or combined neuropeptides in vitro, allowing for differentiation on a neuronal network level. Finally, we provide evidence that the selection of differential combinations through such screening results in more efficacy in food intake and body weight loss. Therefore, this approach not only enables the in vitro profiling of compounds in acute applications but also supports suitable screening for novel combinations within the native hypothalamic or any obesity associated neuronal circuitry, thereby to achieve enhanced synergistic efficacy for anti-obesity treatment in vivo.