A midbrain to ventral striatum dopaminergic pathway orchestrates odor-guided feeding on cotton bollworm larvae in mice

Interspecific interactions are crucial for maintaining ecological balance. Foraging and food consumption are fundamental for the survival of animals. In natural environments, wild rodents feed on various insect species, including moth larvae, and odor-guided evaluation of potential food resources is a critical step in initiating feeding behavior. However, the mechanisms by which rodents seek and feed on insect prey remain poorly understood. Herein, we employed a laboratory-based predator-prey interaction system using mice and cotton bollworm larvae to investigate the neural mechanisms underlying food-seeking and feeding behaviors at both cellular and neural circuit levels. We demonstrate that mice exhibit a strong preference for consuming fed larvae, and this preference is dependent on the main olfactory system. Gas chromatography-mass spectrometry (GC-MS) analysis revealed significant differences in the chemical profiles of fed and unfed larvae, with fed larvae containing a higher level of linoleic acid (LA) and a lower level of (Z)-9-tricosene ((Z)-9-TE). Behavioral assays showed that mice, as well as Brand’s voles and brown rats, are attracted to LA but avoid (Z)-9-TE in a two-choice odor preference test. Furthermore, we identified that the dopaminergic pathway from the ventral tegmental area (VTA) to the medial olfactory tubercle (mOT) plays a central role in mediating this preference. Chemogenetic inhibition of this pathway abolished the preference for LA over (Z)-9-TE, while chemogenetic activation reversed this effect. Additionally, fiber photometry recordings and pharmacology revealed that mOT D1 and D2 spiny projection neurons (SPNs) preferentially mediate attraction to LA and avoidance of (Z)-9-TE, respectively. These findings provide a framework for rodents’ food forage and consumption in the complicated natural environment.