Neuromedin U Acts via the Paraventricular Nucleus of the Hypothalamus and the Dorsal Raphe Nucleus to Regulate Motivation for High-Fat Food

Motivation for high-fat food is thought to contribute to excess caloric intake in obese individuals. A novel regulator of motivation for food may be neuromedin U (NMU), a highly-conserved neuropeptide that influences food intake. Although these effects of NMU have primarily been attributed to signaling in the paraventricular nucleus of the hypothalamus (PVN), NMU has also been found in other brain regions involved in both feeding behavior and motivation. We investigate the effects of NMU on motivation for food and food intake, and identify the brain regions mediating these effects. The motivational state for a particular reinforcer (e.g., high-fat food) can be assessed using a progressive-ratio schedule of reinforcement under which an increasing number of lever presses are required to obtain subsequent reinforcers. Here, we used a progressive-ratio operant responding paradigm in combination with assessments of food intake, craving-like behavior, and locomotor activity to evaluate the effects of NMU in rats, and identify the brain regions mediating these effects. We found that peripheral administration of NMU decreases operant responding for high-fat food in rats. Evaluation of Fos-like immunoreactivity in response to peripheral NMU indicated the PVN and dorsal raphe nucleus (DRN) as sites of action for NMU. NMU infusion into either region mimics the effects of peripheral NMU on food intake and operant responding for food. Moreover, NMUR2 knockdown in the PVN inhibited the incubation of craving-like behavior, suggesting a complex role for NMU in regulating changes in motivation for food. NMU-containing projections from the lateral hypothalamus (LH) to the PVN and DRN were identified as an endogenous source of NMU; a pathway linking the PVN to the nucleus accumbens shell (NAcSh) was identified as a possible downstream mechanism regulating food motivation, and characterized as potentially enkephalinergic. Together, these data suggest a LH-PVN-NAcSh and a LH-DRN pathway as mechanisms for regulating high-fat food craving and motivation through NMUR2.