Neuropeptidergic mechanisms underlying hedonic feeding behavior - PROJECT SUMMARY The motivation to seek food is one of nature’s strongest driving forces and is essential for the survival of any species. Mammals often show an increased motivation to consume calorie-dense food, which is evolutionarily favorable as it allows them to store excessive calories in the form of fat to cope with future food scarcity. Many humans, however, live in conditions where food is readily available and abundant, and the evolutionary drive to take advantage of calorie-dense foods can become maladaptive and promote obesity. The role of the neuropeptide neurotensin (NTS) in feeding and obesity has been studied for decades; however, largely based on its expression in the lateral hypothalamus. We found that NTS is highly expressed in a central node of the brain’s reward system, the lateral nucleus accumbens (NAcLat). NAcLat neurons project to the ventral tegmental area (VTA) and we have previously demonstrated that optogenetic stimulation of the NAcLat→VTA pathway promotes reward-related behaviors. Yet, the function of NTS in the NAcLat→VTA pathway is unknown. In preliminary experiments, we found that optogenetic stimulation of NAcLat terminals in the VTA strongly increased hedonic feeding in mice that are kept on a regular chow diet, but not in mice that are on a high-fat diet (HFD). While the feeding produced by optogenetic stimulation of NAcLat→VTA neurons was restored when HFD mice were placed back on a regular diet for an extended time, optogenetic stimulation of NAcLat→VTA neurons never affected feeding behavior of regular chow. Importantly, optogenetic induced hedonic feeding behavior was prevented by infusion of an NTS receptor antagonist into the VTA suggesting a potential role for NTS in the NAcLat→VTA pathway for hedonic feeding behavior. Based on our preliminary data, we propose to study NTS signaling in the NAcLat→VTA pathway in the context of hedonic feeding behavior and determine pre- and post-synaptic mechanisms of how prolonged HFD may affect this circuitry to promote behavioral and metabolic adaptations. To do this, we have established a collaboration with Lin Tian (Max Planck Florida), who has developed a novel neurotensin sensor that allows us to measure NTS release in vitro and in vivo. We will also collaborate with the lab of Csaba Földy (University of Zurich) to perform patch-seq experiments and analyze diet-induced adaptations in gene expression and cellular physiology. Because many functions of the brain reward circuitry are conserved between mice and humans, our work to understand diet-induced changes in the mouse brain will provide an important foundation for the development of future obesity treatments.
