Neurotensin mediated regulation of hedonic feeding behavior and obesity in mesolimbic circuits

Ventral tegmental area (VTA) dopamine neurons can drive motivated feeding behavior and have receptors for the feeding-related neuropeptide neurotensin (NTS). Lateral nucleus accumbens (NAcLat) express NTS and its inputs to the VTA promote reward and motivation, but whether this pathway influences motivated feeding behavior is unknown. To study the role of the NAcLat→VTA pathway underlying behavior, we performed optogenetic stimulation of the NAcLat→VTA pathway and found that it strongly increased consumption of different types of palatable foods, but not standard chow. Consistent with this, we performed in vivo electrophysiological recordings of opto-tagged NAcLat→VTA units to find that neural activity of NAcLat→VTA units is directly correlated with consumption of palatable food, but not regular chow. Using patch-seq experiments, we found that NTS is highly expressed in ventral tegmental area (VTA)-projecting nucleus accumbens lateral shell (NAcLat→VTA) neurons. We then leveraged a novel neurotensin sensor (ntsLight1.1) to confirm that NTS is released in the NAcLat →VTA pathway. local infusion of an NTS receptor antagonist into the VTA of freely behaving mice prevented hedonic feeding behavior induced by optogenetic stimulation of the NAcLat→VTA pathway indicating that NTS release is essential for regulation of hedonic feeding by NAcLat-> VTA. Intriguingly, in the high fat diet (HFD) obesity mouse model, we found that NTS neurotransmission was reduced in the NAcLat-> VTA pathway following four weeks of HFD. In vivo electrophysiological recording verified in these mice that, unlike during regular diet, NAcLat→VTA unit activity no longer correlated with palatable food consumption. Optogenetic stimulation of the NAcLat→VTA pathway in HFD mice also failed to induce hedonic feeding behavior, however, this effect reappeared when mice returned to a regular diet. Lastly, when we selectively overexpressed NTS in the NAcLat→VTA pathway of mice exposed to HFD, we observed a significant reduction in weight gain compared to control mice. Together, these data reveal an unexpected role for NTS in the NAcLat→VTA pathway for promoting hedonic feeding behavior, which is dependent on the food environment. These findings contrast the well-known anorexic effects of NTS in the lateral hypothalamus suggesting that circuit-specific manipulations of NTS neurons are critical in order to harness the translational potential of NTS in the treatment of obesity.