PROJECT SUMMARY Our modern food environment, with its widespread availability of energy-dense, palatable foods and associated cues, is thought to interact with our physiology to promote food intake. This has contributed to the drastic increase in obesity in the United States over the past several decades. However, most pharmacological weight loss strategies target satiation pathways, not sensory pathways, and therefore may be less effective at eliminating effects of environmental/sensory cues on food intake. Here we propose to take a novel approach to understanding the drive to eat by examining the neural integration of sensory and nutritive food signals. First, we will create sensory “engrams” – functional maps of neurons activated by discrete sensory stimuli – and determine how activating or inhibiting these circuits can influence food preference. This process will reveal the power of leveraging “neural tastes,” “neural smells,” and “neural nutrients” – sensory experiences without external sensory input – to shift feeding behavior. Next, we will monitor neural activity in awake, freely moving mice to determine how neural activity in response to the sensory properties of food relates to individual differences in feeding behavior and future weight gain. Finally, we will monitor calcium dynamics in individual neurons to reveal the activity patterns that integrate sensory and nutritive information in the brain across different body weights. Successful implementation of this proposal has the potential to enable an entirely new line of research and development for weight loss therapeutics that targets neural circuits that integrate sensory and nutritive properties of food. My track record of scientific innovation and productivity, combined with the collaborative environment at the Monell Chemical Senses Center and Department of Neuroscience at the University of Pennsylvania, makes me uniquely suited to bridge the fields of chemosensory biology, feeding neurobiology, and obesity to execute a project of this ambition. Overall, this NIH Director’s New Innovator Award would launch my early career and provide the intellectual space to pursue innovative research that can redefine the neural mechanisms that underlie overeating and obesity.

PROJECT NARRATIVE In our modern food environment, we are constantly exposed to compelling food cues – such as the smell and taste of highly palatable foods – that interact with our physiology to promote feeding and weight gain. Here, we take a unique approach to understanding obesity by (1) evaluating the power of taste, smell, and nutrient neural circuits in modifying eating behavior, and (2) uncovering how sensory and nutritive information is integrated in the brains of awake behaving mice to predict future weight gain. Successful completion of this proposal will transform our understanding of how our brain and environment interact to promote overeating and obesity.